Y/6 and Other Unconventional T Lymphocytes: What Do They See and What Do They Do? Stefan H

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Proc. Natl. Acad. Sci. USA Vol. 93, pp. 2272-2279, March 1996 Review y/6 and other unconventional T lymphocytes: What do they see and what do they do? Stefan H. E. Kautmann* Department of Immunology, University of Ulm, Albert-Einstein-Allee 11, D-89070 Ulm/, Germany; and Max Planck Institute for Infection Biology, Monbijoustrasse 2, 10117 Berlin, GerTnany

ABSTRACT T lymphocytes recognize required to combat the plethora of infec- and that y/8 T cells not only share nu- specific ligands by clonally distributed T- tious agents encompassing virus, pro- merous features with a/P T cells but also cell receptors (TCR). In humans and most karyotes, protozoa, and metaozoa. Thus, possess several unique properties, suggest- animals, the vast majority ofT cells express immunoglobulin (Ig)-producing B lym- ing complementary contributions of both a TCR composed of an a chain and a f3 phocytes, which recognize "their" anti- T-cell types to the immune response. chain, whereas a minor T-celi population is gens directly, are well equipped for de- characterized by the TCRVy/. Almost all of fence against extracellular pathogens. In Vy/ T cells: What Do They See? our knowledge about T cells stems from contrast, T lymphocytes, which are fo- a/13 T cells and only now are we beginning cused on foreign peptides presented by Distribution of a/fl and Vy/ T Cells. to understand y/8 T cells. In contrast to self MHC molecules, are best equipped In humans and the most widely used ex- conventional a/13 T cells, which are specific for dealing with host cells infected with perimental animal in immunology, the for antigenic peptides presented by gene intracellular pathogens. MHC class II mouse, the vast majority of T cells products of the major histocompatibility molecules serve as transporters of pep- (>90%) in peripheral blood and conven- complex, y/ST cells directly recognize pro- tides from endosomal microbes to the cell tional lymphoid organs express the teins and even nonproteinacious phospho- surface leading to CD4 T-cell activation. TCRa/f3 and only a minority (<10%) ligands. These findings reveal that y/8 T Peptides from cytosolic pathogens are express the TCRy/8 (1, 2). In mice, how- cells and a/f8 T cells recognize antigen in a processed through MHC class I, thus stim- fundamentally different way and hence mit- ever, y/6 T cells are a major T-cell pop- ulating CD8 T cells. The CD8 T cells lyse ulation of the epithelia in skin and mucosa igate the dogma of exclusive peptide-major infected host cells and hence are best histocompatibility complex recognition by equipped for antiviral protection, whereas (3, 4). Mucosal epithelia serve as interface T cells. A role for Vy/ST cells in antimicro- CD4 T cells activate effector cells for between the external and internal milieu bial immunity has been firmly established. defence against prokaryotic and eukary- and thus perform important barrier func- Although some y/ T cells perform effector otic pathogens. The so-called Thl cells tions. On the one hand, they prevent entry functions, regulation of the professional secrete interferon 'y (IFN-y) and interleu- of exogenous pathogens and, on the other and the nonprofessional immune system kin (IL) 2, which activate T cells and hand, they must promote entry of solid, seems to be of at least equal importance. macrophages to attack intracellular liquid, or gaseous nutrients. Not surpris- The prominent residence of Vy/ T cells in pathogens of viral, bacterial, or protozoal ingly, the epithelial layers encompass a epithelial tissues and the rapid mobilization origin. On the other hand, IL-4 and IL-5 unique immune system. T lymphocytes, of V/l T cells in response to infection are from Th2 cells stimulate B cells and eo- termed intraepithelial lymphocytes consistent with such regulatory activities sinophils to combat extracellular patho- (IELs), are scattered among and in close under physiologic and pathologic condi- gens, in particular helminths. In contrast contact with epithelial cells. These IELs tions. Thus, although y/8 T cells are a to these well documented precedents of have unique phenotypic and functional fea- minorfraction ofall T cells, they are notjust binary division, the biological relevance of tures that distinguish them from those ofthe uninfluential kin of a/,8 T cells but have the TCR dichotomy is less clear. Antigen central immune system. Although at a given their unique raison d'etre. recognition and functional activities of site only a few IELs are found, the total a/f3 T cells are understood in great depth number of IELs by far exceeds that of all The immune system exists to protect us and, therefore, often generalized to all T lymphocytes in blood and central immune from infectious disease. As a corollary, it cells, whereas those of y/8 T cells have organs, because of the extraordinarily large evolved through constant encounter with largely remained enigmatic. Since fy/8 T size of the mucosal layers. In contrast to microbial pathogens. During this coevo- cells have been identified in all species murine epithelia, a/f3 T cells preponderate lution, many immunologic systems be- that possess a/,3 T cells, however, there in skin and mucosa of humans; yet, even in came dichotomous by nature: the media- appears a logic behind their existence. humans, y/6T cells are more prominent in tors ofspecific immunity encompass T and Although it is now appreciated that y/S T these locations than in peripheral blood and B lymphocytes; two different chain com- cells share numerous features with a/P3 T conventional lymphoid organs. binations of the T-cell receptor (TCR) are cells, we know very little about their used for antigen recognition, TCRa/13 unique capacities. Are these cells just re- and TCR-y/S; the so-called T cells fall dundant remnants that recognize similar Abbreviations: 132m, 132-microglobulin; D, di- a/,B versity; Hsp, heat shock protein; IEL, intraepi- into CD4 T cells, which are restricted by antigenic ligands in the context of MHC thelial lymphocyte; IFN-'y, interferon y; Ig, major histocompatibility complex (MHC) products as a/f3 T cells do? Do they immunoglobulin; IL, interleukin; J, joining; class II gene products, and into CD8 T principally perform similar biological MHC, major histocompatibility complex; NK, cells, which are restricted by MHC class I functions as a/j3 T cells do, but just at natural killer; TCR, T-cell receptor; Th, T molecules; according to their cytokine other locations and at other time points of helper; V, variable; DN, double negative; mAb, monoclonal antibody; TNF-a, tumor necrosis patterns, CD4 T cells are T helper (Th) 1 the immune response? Or, alternatively, factor a. or Th2 type. This dichotomy appears as an are there more profound differences be- *To whom reprint requests should be addressed appropriate compromise between the tween -y/8 T cells and a/P3 T cells? Most at: Department of Immunology, University of specification and the generalization that is recent findings suggest that both are true Ulm, D-89070 Ulm, Germany. 2272 Downloaded by guest on September 26, 2021 Review: Kaufmann Proc. Natl. Acad. Sci. USA 93 (1996) 2273

Development of TCRy/8 Diversity. As Human y/5 T cells use one of two Table 1. Correlation of two major holds true for the other antigen-specific different VS chains, V81 or V82 (1). In the nomenclatures for murine TCRVy genes receptors-Ig and TCRa/f-the TCR-y peripheral blood of human adults, >70% V,y designation and 8 chains undergo rearrangements to of all y/6 T cells express the V62 chain, achieve clonal specificity (1). Contrary to whereas the remaining -30% are V81+. Garman et al. (134) the generally held view, it appears that the This is in contrast to the thymus and cord and TCRy/S not only shares important fea- blood where V81 cells preponderate over Heilig et al. (133) Asarnow et al. (135) tures with the TCRa/,B but also resembles V82 cells. Peripheral blood y/8 T cells of 1 1.1 Ig in important aspects (5, 6). Moreover, human adults coexpress the V62 chain in 2 1.2 several unique features are involved in combination with Vy9, whereas V81 com- 3 1.3 TCR,y/6 specificity. Because numbers of bines with one ofvarious Vy chains. (Note 4 2 the variable (V), diversity (D), and joining that two nomenclatures are currently in 5 3 (J) gene segments for TCRy/8 are low, use for human Vy so that Vy9 may also be 6 4 rearrangements alone are insufficient for referred to as V-y2 in the literature.) 7 5 creating an equally large diversity as they In mice, three types of -y/8 T-lympho- do in Ig and TCRa/3. However, a simi- cyte sets can be distinguished (1). The first tinal epithelium. The y/8 T cells found in larly large repertoire is achieved by addi- set matures in the fetal thymus in a de- the lung and other epithelia are either tional mechanisms, in particular the gen- velopmentally ordered fashion. It is char- monospecific or highly diverse. Thus, the eration of immense junctional diversity acterized by its selective homing to and y/8-T-cell population as a whole encom- due to N-nucleotide insertions at up to residence in defined epithelial tissues. passes the entire array of antigen specificity three V/D/J joining sites. They form the These cells rearrange unique TCRy/8 ranging from monospecificity to extreme complementarity determining region 3 genes with canonical junctional se- diversity. As a corollary, antigen presenta- (CDR3) as major binding site of quences, suggesting essentially mono- tion to 'y/8 T cells must be of resiliency TCRy/8 specificity. The Vy5 cells localize to the similar to the TCRy/8 itself ranging from for antigenic determinants. The CDR3 of skin, whereas those expressing Vy6 home monomorphic to polymorphic antigen- TCR,y/8 shows greater similarity to Ig to and reside in mucosal tissues of vagina, presenting molecules and encompassing than to TCRa/,. Its structural features uterus, and tongue. (For an alternative even direct antigen recognition. suggest that it accommodates a larger nomenclature, see Table 1.) The second Antigen Recognition. Few immune variety of antigenic ligands and binds an- set of y/8 T cells develops in the adult mechanisms have been considered as tigen directly and independently from an- thymus. Cells of this set preferentially use abiding as antigen recognition by T cells. tigen-presenting molecules (5, 6). Yet, V'yl or Vy4 and less frequently Vy2 or The trimolecular complex ofTCR, foreign high variability is not generated in all y/8 V,y7 and they express an enormous anti- peptide, and self MHC is generally viewed T cells and seems to be irrelevant to most genic repertoire due to extensive junc- as one of the few central laws of cellular prominent stimulatory ligands of y/8 T tional diversity. These y/8 T cells prepon- immunology (8). Recent insights into an- cells known thus far that resemble superan- derate in peripheral blood and conventional tigen recognition by y/8 T cells, however, tigens functionally. Superantigens stimulate lymphoid organs and may occasionally lo- have violated this law. This mitigation has a large proportion of a/3 T cells by calize to certain mucosal tissues. The third been further exacerbated by the realiza- crosslinking the MHC class II gene product set of y/S T cells appears to develop thymus- tion that a small population of a/P T cells on stimulator cells with a number of TCRf3 independently. These cells preferentially use also fails to obey the dictate of MHC- chains independent from fine antigen spec- V,y7 and Vyl with high junctional diversity restricted peptide recognition. The fol- ificity via a conserved binding site (7). and are preferentially localized in the intes- lowing discussion, therefore, includes Antigen

Processed Free Super- Antigen Antigen antigen

MHC Other

FIG. 1. Scheme depicting the plentitude of conventional and unconventional T-cell populations and their stimulatory ligands. The nonpeptide ligands recognized by human DN TCRa/, cells in the context of CDlb encompass mycobacterial mycolic acid and lipoarabinomannan; the phospholigands recognized by human TCR-y/8 cells include isopentenyl pyrophosphate and other phosphorylated alkyls, phosphorylated carbohydrates, or nucleotidic pyrophosphodiesters. Murine CD8 TCRa/, cells probably recognize peptidic and nonpeptidic ligands presented by MHC I-like molecules. Stimulation of TCRy/S cells by nonpeptidic ligands in the context of MHC I-like molecules appears possible, although direct evidence is still missing. Downloaded by guest on September 26, 2021 2274 Review: Kaufmann Proc. Natl. Acad. Sci. USA 93 (1996)

these unconventional a/3 T cells that associated antigen-presentation pathways cell membrane, no evidence for conven- characteristically lack both CD4 and CD8 (19, 20). Although evidence is still scarce, tional antigen processing or for the in- and hence are termed double negative it is, therefore, tempting to consider even volvement of MHC, MHC-like, or CD1 (DN). Presentation of antigenic peptides MHC unrelated antigen recognition by molecules has been obtained (see Fig. 1) to the vast majority of a/13 T cells is -y/5 T cells. For the following reasons, the (46). It therefore appears that this mole- afforded by highly polymorphic classical NRAMP gene product represents an in- cule is recognized directly by the TCRy/8 MHC molecules. The MHC class II a/13 teresting candidate of this conjectural provided it is anchored to the target cell heterodimer is responsible for presenta- group of antigen-presenting molecules in surface by thus far unknown mechanisms. tion of endosomally derived peptides to mice: The NRAMP gene encodes a trans- Stimulation of murine y/6 T cells by lipo- CD4 TCRa/13 cells; the MHC class Ia porter molecule that has been implicated polysaccharide through an apparently chain in association with the non-MHC- in innate resistance to intracellular micro- TCR-independent mechanism has been encoded f32-microglobulin (f32m) presents bial pathogens, including Salmonella sp. described, but convincing evidence for cytosolic peptides to CD8 TCRa/13 cells and Mycobacteria sp. (21). The y/6 T cells TCR-mediated stimulation of murine y/6 (8). The highly polymorphic MHC mole- contribute to early resistance against such T cells by nonproteinaceous ligands does cules embrace the huge antigenic reper- pathogens and differential y/8-T-cell re- not exist (47). toire of conventional a/X3 T cells. On the sponses to Salmonella sp. have been de- Recently, human TCRa/f3 cells have one hand, this almost unlimited epitope scribed in susceptible and resistant mouse been detected that are stimulated by non- coverage has provided a comprehensive strains (22-24). Moreover, evidence for proteinaceous microbial components in shield against microbial pathogens that -y/5-T-cell surveillance of hematopoietic the context of CDlb (48-50). Most of create an unending antigenic variation by tumors has been presented that is MHC- them are DN although some cells may mutation. On the other hand, exclusion of independent and NRAMP-dependent express CD8. Two stimulatory ligands self-reactive a/,3 T-cell clones became an (25). Perhaps the NRAMP gene product have been identified thus far, namely, essential to avoid the "horror autotoxi- participates in the transport to the cell lipoarabinomannan and mycolic acids, cus" of autoimmune disease. Besides, a surface of microbial and tumor-specific that represent major constituents of the second set of surface molecules exists that ligands for y/8 T cells. The availability of waxy cell wall skeleton of mycobacteria presents antigenic ligands to rare T cells, NRAMP gene deletion mutants will allow (48, 49). Both lipoglycans are unique to such as -y/8 T cells and DN a/13 T cells, yet experimental verification of this proposi- the Mycobacteriaceae and a few related shows no or a low degree of polymorphism tion (26). Evidence is increasing that mu- families and are clearly absent in humans (9-11). Similar to MHC class I molecules rine -y/8 T lymphocytes even recognize (51). Mycolic acids are long-chain fatty virtually all of these unconventional pre- surface-expressed proteins directly and in- acids in mycobacteria that are typically sentation molecules are surface-expressed dependently from antigen-processing and esterified to arabinogalactan or to treha- in combination with 932m. The MHC class MHC presentation (6, 27). Although lose. The latter molecule, 6,6'-trehalose I-like gene products are encoded inside some of the murine -y/8 T cells analyzed dimycolat, termed cord factor, has been and the CD1 molecules are encoded out- recognize MHC class II (H-21-E) or an used as potent immunomodulator for a side the MHC locus. This nonpolymorphic MHC class I-like molecule (TL), the bind- long time. Lipoarabinomannan is a com- T-cell control is ineffectual in covering a ing site was peptide-independent and out- plex glycolipid. Further characterization similar plethora of antigenic ligands as is side ofthe peptide binding cleft (6, 28, 29). of the active component pointed to afforded by the polymorphic MHC restric- Similarly, a herpes virus protein was found a(1->2)-linked mannosides and phospha- tion and rather has to pick selected li- to directly stimulate y/6 T cells indepen- tidylinositol as crucial elements for stim- gands. Fig. 1 gives an updated overview dent of antigen processing and presenta- ulation. Although the CD1 molecules are about various forms of antigen presentation (30). Hence, this type of encounter of nonpolymorphic, current evidence sug- tion and stimulation of T-cell sets. the TCR-y/8 with its ligand resembles gests that DN a/13 T cells express fine Murine and human -y/S T cells that are antigen-antibody interactions. At least antigen specificity and, hence, are induced stimulated by peptides in the context of some of the earlier findings describing in an antigen-specific rather than superan- MHC class I or class II molecules have recognition of CDlc, CD48, or Hsp6O by tigen-like fashion (9, 48, 49). Absence been described, demonstrating that con- human y/8 T cells may be interpreted to from human cells and chemical nature of ventional antigen recognition by y/8 T mean direct interactions between TCR these glycolipids apparently exclude the cells exists (12-15). Yet, far more y/6 T ,y/6 and these molecules (31-34). risk of autoimmune responses but also cells were found to be MHC independent. In 1990, stimulation of human y/8 T raise many questions about selection of Murine y/8 T cells have been indentified cells by apparently nonproteinacious low this unconventional TCRa/j3 repertoire. that are under the control of the MHC molecular weight ligands was described Obviously, conventional thymic selection class I-like gene Qa-1 within the H-2T (35). These ligands were originally iso- can be excluded unless one assumes the locus (T23) (16). Such y/8 T cells can lated from Mycobacterium tuberculosis and unlikely possibility of conformational recognize synthetic poly(Glu-Tyr) in a later defined as the major stimulatory mimicry with self peptides. processing-independent fashion (16). The components of this and many other patho- CD1 molecules are surface-expressed in Qa-1 product, therefore, seems to present genic and nonpathogenic bacteria and association with g2m as are MHC class I much larger polypeptides to y/8 T cells even protozoa (36-40). It was then found molecules, but processing of the mycobac- than the classical MHC molecules to con- that phosphate is an essential component terial lipoglycans was blocked by pharma- ventional a//3 T cells. In another experi- that can be bound to an alkyl, carbohy- cologic agents that interfere with the en- ment, preferential binding to the Qa-1 drate, or nucleotide residue (41-45). Ac- dosomal processing pathway involved in molecule of heat shock protein (Hsp) 60 cordingly, I shall term this heterogeneous MHC class II peptide processing (49). peptides was described (17, 18). Hsp6O group of major y/6-T-cell stimulators Moreover, presentation of glycolipids by peptides may represent preferred ligands for phospholigands. Most recently, the first CDlb was independent of mechanisms a subset of murine y/6 T cells (see below). natural phospholigand has been chemi- participating in antigen processing through Virtually normal levels of y/8 T cells in cally identified as isopentenyl pyrophos- MHC class I and class II. These findings f32m gene disruption mutant mice lacking phate, which represents a ubiquitous me- strongly suggest a unique processing path- surface-expressed classical MHC class I tabolite of various vitamins, lipoids, and way specialized to glycolipids and perhaps molecules, as well as MHC I-like and CD1 steroids, both in prokaryotic and eukary- other hydrophobic ligands and involving gene products, strongly suggest virtual in- otic cells (44). Although isopentenyl py- CDlb molecules as presentation elements. dependence of y/8 T cells from 32m- rophosphate must be bound to the host In mice, a CDlb homolog does not exist (9). Downloaded by guest on September 26, 2021 Review: Kaufmann Proc. Natl. Acad. Sci. USA 93 (1996) 2275

In summary, these data demonstrate that A X the paradigm of peptides as exclusive li- a gands for T cells must be given up and that

.. .. the antigenic scope of T cells must be ex- I tended to nonpeptides. The only CD1 gene product CDld (CD1.1 and CD1.2) in mice has been / >1' implicated recently in stimulation of an- 'ii / other unconventional a//3 T-lymphocyte V.A' / / . .7 set characterized by the phenotype CD8-, Y 6 Y: 6 y CD4+/- NK1+ (52), where NK is natural 6 killer. The cells are potent IL-4 producers and thus promote Th2 cell development (53, 54). Although indirect evidence suggests that these T cells recognize hydrophobic self peptides, presentation of non- 20 peptide ligands by murine CDld cannot be excluded at present (55). In the model '-.,'.( )//. of Listeria monocytogenes infection of /x>/h mice, CD8 TCRa/13 cells have been iso- s. c lated that recognize listerial antigens in the context of the nonpolymorphic MHC B I-like gene product, H-2M3 (56-58). The stimulatory ligands have been identified 10 as N-formylated peptides that represent conserved signal sequences for secreted proteins in prokaryotes. Moreover, tenta- tive evidence suggests that nonpeptides- l I probably carbohydrates-from L. monocytogenes can be presented in the context of H-2M3 gene products (R. Kurlander and K Y /i Fischer-Lindahl, personal communication). Kt\ y Oligoclonal Stimulation and Its Impact on Peripheral y/6 T-Cell Development At I 'VI/ \",, and Function. Among the known ligands for y/8 T cells, two have gained particular /1'' reputation because of their wide distribu- //\I tion in the biosphere and oligoclonal stim- , <5! ulation of y/8 T cells. These are the Hsps y b Y and the phospholigands. In mice a high proportion of ry/8 T cells has been identi- FIG. 2. Scheme describing two types of TCRy/8-mediated T-cell stimulation. (A) Stimulation fied that not only respond to unique pep- of y/8 T cells by antigen-specific ligands that bind to a highly diverse TCRy/8 site. Ligands include tides of mycobacterial Hsp6O but also peptide plus presenting molecule (MHC, MHC-like, or CD1) or protein proper. Primary recognize autologous host cells in the stimulation causes monoclonal expansion of y/8 T cells expressing a unique TCR. Activated y/8 T cells, therefore, are restricted to the primary determinant. (B) Stimulation of 'y/8 T cells by absence of foreign peptides (59-62). Al- ligands that bind to an invariant site on distinct TCRy/8 isotypes. Ligands include phospholigands though the presenting molecules have not (human Vy9) and Hsp peptide (murine Vyl). Primary stimulation causes oligoclonal expansion been definitely defined, classical MHC of y/8 T cells expressing diverse TCRy/8. Activated y/8 T cells, therefore, may respond to various gene products can be excluded and tenta- determinants. tive evidence implicates the MHC I-like Qa-1 gene product (18). Hsps are ubiqui- cells. Rather, a stereotype response Murine Hsp-reactive -y/S T lympho- tous and highly conserved proteins (63). against stressed epithelial cells expressing cytes characteristically express Vyl with The mycobacterial Hsp6O shares a high unique ligands should promote surveil- junctional V/J diversity (59). Yet, these sequence homology not only with its bac- lance functions by y/8 IELs. Although diverse y/8 T cells respond to a unique terial but also with its mammalian cog- principally based on a peptide-specific re- amino acid core sequence of Hsp6O, sug- nates. Although Hsps perform important sponse, the ubiquitous presence of Hsps gesting oligoclonal activation (60). Hence, housekeeping functions, they are ex- could promote broad immune surveil- crossreactivity toward shared epitopes of pressed at elevated levels under stress. lance functions of y/5 T cells. In this Hsp need not necessarily explain recogni- These findings led to the suggestion that concept, y/8 T cells are primarily focused tion of stressed host cells by Hsp-stimu- focus of -y/l T cells on Hsp would promote on self Hsp and recognition of bacterial lated T cells. Rather, it is conceivable that a rapid response to cell stress caused by a Hsp would represent a fortuitous crossre- Hsp peptides stimulate y/8 T cells of variety of insults including infection, in- activity that might further contribute to various unrelated fine specificities encom- flammation, and transformation. Such a antimicrobial immunity. On the other passing yet unidentified antigenic deter- stereotype response of y/6 T cells against hand, the host would carry along the risk minants on host cells (Fig. 2). In support stressed host cells would gain particular of autoimmunity as a consequence of fre- of this, the minimal amino acid sequence relevance for IELs with their sessile loca- quent contact with microbial Hsps, be- of mycobacterial Hsp6O recognized by y/l tion amid epithelial cells. Recognition of a cause of their high conservation. Consis- T cells is not shared with mammalian Hsps large variety of specific ligands from mi- tent with this notion, accumulation of (60). This assumption does not exclude crobial pathogens could hardly explain Hsp-reactive -y/8 T cells has been de- that Hsp peptides themselves are recog- antigen-specific activation of such se- scribed in inflammatory lesions of infec- nized specifically by some of the oligo- cluded and sometimes monospecific y/3T tious and autoimmune etiology (13, 64). clonally activated y/8 T cells. Downloaded by guest on September 26, 2021 2276 Review: Kaufmann Proc. Natl. Acad. Sci. USA 93 (1996)

Although human y/6 T cells that re- produced by stimulated y/5 T lympho- an auxiliary role for y/S T cells was de- spond to Hsp6O have been described nu- cytes (24, 73-77). Production of Th2 type termined (24, 103-106). Both TCR8 and merously, their frequency seems to fall cytokines was less frequently noted. How- TCRI3 gene deletion mutants proved into the range expected for conventional ever, this could be related to the fact that rather resistant to experimental listeriosis antigen-specific T cells (13, 37, 65). Thus, bacteria that are generally potent inducers (24). However, additional treatment of the unique predilection of y/6 T cells for of Thl type responses have been most TCRf3-deficient mutants with anti- Hsp seems to be restricted to the murine widely used as stimulating agents, in both TCR,y/8 mAbs rendered these mice sus- system. Yet, a comparable situation exists the murine system and the human system. ceptible to listeriosis. These findings sug- in humans. Many bacteria have been A more careful study on this topic re- gest that y/6 T cells participate in antimi- shown to exclusively stimulate fy/8 T cells vealed that infection with the intracellular crobial immunity but that they primarily expressing the V-y9V62 combination with bacterium, L. monocytogenes, a character- perform compensatory functions in the high junctional diversity (Fig. 2 and refs. istic Thl inducer, stimulated IFN--y- absence of a/13 T cells. Consistent with 36 and 66-68). Selective expansion of the producing -y/8 T lymphocytes, whereas this notion, y/8 T cells gain importance in V-y9V82 subset occurs in the periphery as the helminth Nippostrongylus brasiliensis f32m-deficient mice lacking CD8 T cells a consequence of continuous encounter preferentially induced a Th2 type re- (20, 107, 108). The -y/6 T cells seem to with various microorganisms (69). Consis- sponse dominated by IL-4 (76). Thus, the contribute to protection prior to a/fl T tent with this assumption, the V82 subset Thl/Th2 dichotomy originally described cells (22, 24) and evidence has been ob- is primarily of memory and the V&1 of for CD4 Th cells also seems to exist for tained for superior extravasation into in- naive phenotype according to expression -y/l T cells. flammatory foci of y/8 T cells as com- or absence of the CD45RO marker (70). Stimulated y/8 T cells generally display pared to a/,B T cells (109). Accordingly, As a corollary, we have to assume that cytolytic activities (1, 38, 73, 78, 79). Fre- the impact of y/5 T cells is small to microbes shape the peripheral y/8 T-cell quently, target cell lysis is not restricted to negligible in secondary infections. In a repertoire in humans. Although not for- the stimulating antigenic ligands. Yet, this similar vein, -y/8 IELs rather than a/13 mally proven, it is safe to assume that the broad reactivity is different from conven- IELs seem to be involved in regional described phospholigands are primarily, if tional lymphokine-activated killer or NK protection against intestinal invasion by not exclusively, responsible for oligoclonal activity. In the human system, oligoclonal food-borne pathogens (95, 111, 112). expansion of V-y9V52 T cells. Human V-y9VS2 T-cell stimulation by phospholi- These findings can be interpreted to mean V-y9V62 T cells stimulated with mycobac- gands is probably the underlying mecha- that y/8 T cells primarily differ from a/13 teria recognize various tumor cells and nism. Yet, specific activities have been T cells in their kinetics and localization Hsps have been implicated in this cross- described occasionally (38, 73, 78). It is rather than in their effector functions. reactive response (34, 71). It remains to be conceivable that these specific activities Evidence for a unique role of y/8 T cells established whether the human TCRy/8 are generally covered by oligoclonal reac- in antimicrobial immunity, however, is "sees" a specific antigenic determinant of tivities of -y/S T cells stimulated by crude accumulating. Thus, in experimental lis- Hsp proper or whether Hsps are involved bacterial preparations and hence are only teriosis, absence of y/8 T cells results in in the transport to or the expression on the detected by preparations devoid of oligo- the rapid formation of abscesses rather surface of host-derived phospholigands. clonal stimulators. than granulomatous lesions (24, 99). Ap- Despite the enormous physicochemical y/6 T Cells in Microbial Infections. On parently, abscess formation does not sig- differences between phospholigands and the basis of several lines of evidence, a nificantly affect bacterial control, since Hsp6O peptides, these ligands share im- particular impact of -y/8 T cells on immu- TCR&-deficient and control mice suffered portant features that could predestine nity against intracellular microbial patho- from an equal listerial load. In a similar them as prototypes of a new group of TCR gens was assumed rather early in the pub- vein, the parasite load of TCRa-deleted ligands (Fig. 2). Direct interactions of lic life of fy/8 T lymphocytes (80). (i) By mice suffering from intestinal infection both ligands with the TCRy/6 have been 1990, evidence from murine and human with Eimeria vermiformis is not elevated as proven by using TCR transfectants (60, systems had emerged to suggest that my- compared to controls (A. Hayday, per- 72). (i) They stimulate various junctionally cobacteria are particularly potent stimu- sonal communication). Yet, dramatic diverse T-cell clones expressing a given Vy lators of -y/l T cells (13, 35, 37, 81, 82). (ii) pathologic alterations of the gut epithelia chain (human V-y9 for phospholigands Accumulation of y/8 T cells at certain are evident. Perhaps most impressively, and murine Vyl for Hsp peptides) encom- sites of microbial replication as well as TCRS gene deletion mutants succumb to passing a conserved binding site and in selective y/8-T-cell expansion in periph- M. tuberculosis infection, which is toler- this respect resemble conventional super- eral blood or lymphoid organs have been ated by immunocompetent controls (113). antigens for a/fB T cells (7). (ii) In contrast observed in patients suffering from vari- These findings suggest unique functions of to bacterial superantigens, they are dis- ous bacterial or protozoal infections as y/ T cells in antimicrobial immunity, the tributed ubiquitously in the biosphere well as in numerous murine infection sequelae of which may be overtly protec- ranging from microbial pathogens to models (23, 40, 64, 82-96). (iii) Preferen- tive, such as in experimental tuberculosis, mammalian cells. Therefore, the impact of tial localization of y/8 T cells in epithelial or include a pathologic component as in such ligands shared by microbe and host layers was taken as evidence for their listeria and eimeria infection. on extrathymic 'y/8 T-cell selection, im- surveillance functions at these important Regulatory Functions of y/6 T Cells. mune surveillance, antiinfective protec- sites of microbial entry (97). (iv) Involve- Increasing evidence suggests that -y/l T tion, and development of autoimmune ment of y/8 T cells in antimicrobial immu- cells play a decisive role in maintenance of disease deserves further investigation. nity was directly suggested by experiments host cell integrity and in homeostasis, not in which mice were treated with TCR-y/& only of the professional but also of the 'y/l T Cells: What Do They Do? specific monoclonal antibodies (mAbs). nonprofessional immune system. Lipo- Treatment with anti-TCR-y/6 mAbs ex- polysaccharide is a potent macrophage Functional Activities. Virtually all acerbates experimental infections of mice activator that stimulates production of cy- known major a/fl T-cell functions have with various bacterial and protozoal tokines, such as tumor necrosis factor a been described for ry/5 T lymphocytes. pathogens (22, 96, 98-100). Further in- (TNF-a). Macrophages from -y/5-T-cell- That is, -/A T cells secrete various cyto- sights became possible with the availabil- deficient mutant mice are largely curtailed kines and express cytolytic functions. In ity of TCRfI and TCR8 gene disruption in their TNF-a production, suggesting a the majority of studies, Thl cytokines, in mutants lacking a/fl or y/8 T cells, re- regulatory role of y/8 T cells in macro- particular IFN-,y, have been shown to be spectively (101, 102). In various models, phage activation (114). Consistent with Downloaded by guest on September 26, 2021 Review: Kaufmann Proc. Natl. Acad. Sci. USA 93 (1996) 2277

these in vitro findings, TCRS gene deletion their quantitatively unequal distribution, tification of nonproteinaceous T-cell an- mutants proved more resistant to septic y/8 T cells and a/,3 T cells appear to be tigens in pathogenic mycobacteria has shock by a Gram-negative bacterium than engaged in an ardent crosstalk that keeps added a new dimension to these specula- controls (88). Abundant TNF-a produc- the immune system in balance. The sur- tions. Although proteins will last as the tion is a harmful sequela of septic infec- prising finding is the paucity of y/8 T cells major antigens for new vaccines, nonpro- tions with Gram-negative bacteria, sug- that are capable of regulating the much teins cannot be ignored any longer. Two gesting that impaired TNF-a production larger population of a/,3 T cells. opposite possibilities must be considered. in the absence of -y/8 T cells allows escape The y/8 T cells are relatively prevalent Because of the ubiquitous presence and from deterimental TNF responses. Al- in various epithelial tissues where they live superantigen-like activities of the phos- though TCR8-deficient mice are as resis- a more sessile life (3, 4, 122). The so-called pholigands, the repertoire of activated tant to listeriosis as their heterozygous dendritic epidermal y/5 T cells in the skin V,y9V82 T cells may contain host antigens. littermates, they transiently suffer from of mice express an invariant TCR-y/l and Hence, the possibility exists that autoag- exacerbated listeriosis at the outset of are in close contact with keratinocytes (4). gressive y/6-T-cell responses are activated infection. This elevated susceptibility is Stressed keratinocytes are recognized by by a vaccine containing phospholigands. correlated with impaired IFN-,y produc- dendritic epidermal y/8 T cells and rec- In support of this, an association of tion by NK cells (C. H. Ladel and ognition may involve self Hsps (123). This V,y9V82 T cells with autoimmune disease S.H.E.K., unpublished data). Thus, it ap- interaction causes skin TCRy/8 IELs to has been claimed (13). If this alternative pears that y/S T cells control rapid acti- produce a keratinocyte-specific growth turns out to be correct, subunit vaccines vation of NK cells in response to microbial factor (124). The factor is also produced devoid of nonproteinaceous ligands infection. TNF-a and IFN-y are crucial by intestinal -y/l IELs, but not by splenic should be favored. Interestingly, culture for the formation of granulomatous le- ,y/8 T cells or by intestinal a/f3 IELs. conditions can be established that inter- sions (80). Impaired TNF-a and IFN-y Hence, this factor seems to be unique to fere with synthesis of phospholigands in production at the onset of infection, there- epithelial -y/S IELs. It acts as growth mycobacteria (B. Schoel and S.H.E.K., fore-at least partially- could explain the factor for epithelia at various sites, includ- unpublished data). Consequently, these formation of abscesses rather than gran- ing the intestine. In mice and humans mycobacterial preparations are devoid of ulomas in L. monocytogenes-infected close contact between IELs and intestinal oligoclonal y/5-T-cell stimulating activity. TCRS gene deletion mutants (24, 99). epithelial cells is promoted by specific At the other extreme, nonproteina- To protect the host from undesired adhesion molecules, namely aE37 integrin ceous ligands provide their share in pro- immune responses against food-derived on IELs and E-cadherin on enterocytes tection. Subunit vaccines composed of re- proteins, oral tolerance mechanisms must (125, 126). This heterophilic adhesion combinant proteins would then be insuf- be induced by the intestinal immune sys- mechanism may not only promote selec- ficient and nonproteinaceous ligands must tem (115). At least in part, oral tolerance tive immigration into and retention in the be added. The glycolipids, lipoarabino- is maintained by the predominant Th2 gut of intestinal IELs but also support mannan and mycolic acids, that stimulate over Thl responses to antigens present in functional interactions between both cell DN a/P T cells do not exist in mammalian Peyer's patches. Although intestinal IELs types. By using TCRS-deficient mutant cells and even among prokaryotes they are expressing either TCRa/f3 or TCR-y/8 mice, evidence for reduced epithelial cell quite unique to mycobacteria and few produce a similar array of cytokines of the turnover in the intestine in the absence of other species. Hence, they represent ideal Thl and the Th2 type, evidence has been ,y/8 IELs has been obtained (127). These nonself antigens, something a conven- presented that y/S IELs in the gut abro- findings strongly suggest that 'y/8 T cells tional protein antigen can never assert. gate oral tolerance, whereas a/,B IELs maintain epithelial integrity by promoting Such unique mycobacterial antigens, with- promote humoral responses (116, 117). In homeostasis and immune surveillance. out doubt, represent interesting candi- the respiratory tract, a similar mechanism Consistent with this notion is the exacer- dates for new antituberculosis (or antile- seems to be in effect that counteracts the bated intestinal bleeding in TCR6-/- prosy) vaccines. Since these ligands are development of IgE-mediated allergic re- gene disruption mutants as a consequence presented by the nonpolymorphic CD1 sponse. It appears that these IgE re- of eimeria infection (see above) and the gene products, concerns about genetic sponses to inhaled antigens are sup- selective increase of intestinal y/8 IELs in variations among vaccinees are obsolete pressed by a control mechanism that is coeliac disease patients (128). as they hold true for peptide-based vac- reminiscent of the Thl/Th2 balance Implications for Vaccine Development. cines because of the highly polymorphic known from other systems (118, 119). As discussed in the previous paragraphs, classical MHC molecules. While in the lung Th2 activities are asso- (i) 'y/5 T cells are expanded in tuberculo- ciated with conventional CD4 TCRa/f3 sis, (ii) 'y/8 T cells are essential for pro- Concluding Remarks cells, Thl activities are selectively induced tection against murine tuberculosis, and in -y/l T cells. As a corollary, Thl/Th2 cell (iii) DN -y/8 and a/,B T cells are stimulated In beginning this review, I raised the ques- development seems to be regulated differ- by mycobacterial nonpeptide ligands in tion whether y/8 T cells are less influen- ently in -y/S and a/3 T cells. Control of a/13 the apparent absence of presenting mole- tial kin of a/f T cells that just use another T cells by y/6 T cells could play an impor- cules or in the context of CD1 gene prod- receptor or, alternatively, whether they tant role not only in immune homeostasis ucts. These findings have implications for have their unique raison d'etre. Without but also in prevention of allergic diseases. rational design of effective vaccines doubt, there is an overlap among a/f3 and Treatment of naive immunocompetent against tuberculosis and probably other ,y/8 T cells that may cause the overrating mice with anti-TCRy/6 mAbs markedly infectious diseases. Tuberculosis imposes of the more abundant a/13-T-cell popula- activates a/P T cells as determined by IL-2 an enormous threat to public health and tion. Yet, a niche exists for y/8 T cells, the production and target cell lysis in vitro would best be controlled by vaccination relevance of which must not be deduced (120). These findings provide strong evi- (129, 130). It may be worthwhile to remind from our lack of knowledge. Unique re- dence for homeostatic regulation of a/, T the reader less familiar with the work on sponses to antigenic ligands of -y/6 T cells cells by y/S T cells. Evidence for recipro- "tuberculo-immunity" of the continuous have provided a move from the MHC/ cal control of -y/5 T cells by a/13 T cells discussions about nonproteins as protec- peptide/TCR paradigm of specific T-cell stems from studies using TCRa gene dis- tive antigens against tuberculosis (131). responses (132). This move was brought ruption mutants (121). In these a/f-T- Although the proponents of such a view even a step further by the parallel identi- cell-deficient mice, the y/6 T cells un- failed to base their arguments on solid fication of a/P T cells that specifically dergo excessive expansion. Hence, despite scientific grounds until recently, the iden- recognize CD1/glycolipids. Probably, this Downloaded by guest on September 26, 2021 2278 Review: Kaufmann Proc. Natl. Acad. Sci. USA 93 (1996)

distinct type of antigen recognition has its 19. Raulet, D. H. (1994) Adv. Immunol. 55, 46. Morita, C. T., Beckman, E. M., Bukowski, biological basis that is still incompletely 381-421. J. F., Tanaka, Y., Band, H., Bloom, B. R., 20. Ladel, C. H., Flesch, I. E. A., Arnoldi, J. & Golan, D. E. & Brenner, M. B. (1995) Im- understood. However, it is becoming in- Kaufmann, S. H. E. (1994) J. Immunol. 153, munity 3, 495-508. creasingly clear that prominent residence 3116-3122. 47. Leclercq, G. & Plum, J. (1995) J. Immunol. in epithelial tissues and rapid mobilization 21. Vidal, S. M., Malo, D., Vogan, K., Skamene, 154, 5313-5319. of y/8 T cells at the outset of infection are E. & Gros, P. (1993) Cell 73, 469-485. 48. Beckman, E. M., Porcelli, S. A., Morita, coupled with unique biological features. 22. Hiromatsu, K., Yoshikai, Y., Matsuzaki, G., C. T., Behar, S. M., Furlong, S. T. & Bren- Ohga, S., Muramori, K., Matsumoto, K., ner, M. B. (1994) Nature (London) 372,691- They require strong focus not only on the Bluestone, J. A. & Nomoto, K. (1992) J. Exp. 694. professional but also on the nonprofes- Med. 175, 49-56. 49. Sieling, P. A., Chatterjee, D., Porcelli, S. A., sional immune system, in particular epi- 23. Emoto, M., Danbara, H. & Yoshikai, Y. Prigozy, T. I., Mazzaccaro, R. J., Soriano, thelial and endothelial cells, as the first (1992) J. Exp. Med. 176, 363-372. T., Bloom, B. R., Brenner, M. B., Kronen- cells that are confronted with microbial 24. Mombaerts, P., Arnoldi, J., Russ, F., berg, M., Brennan, P. J. & Modlin, R. L. Tonegawa, S. & Kaufmann, S. H. E. (1993) (1995) Science 269, 227-230. infections. Considering disturbance of Nature (London) 365, 53-56. 50. Porcelli, S., Morita, C. T. & Brenner, M. B. host homeostasis as a major factor of 25. Penninger, J. M., Wen, T., Timms, E., Pot- (1992) Nature (London) 360, 593-597. infection, one realizes that similar, not ter, J., Wallace, V. A., Matsuyama, T., Fer- 51. Brennan, P. J. & Nikaido, H. (1995) Annu. disparate, skills are required in both op- rick, D., Sydora, B., Kronenberg, M. & Mak, Rev. Biochem. 64, 29-63. erations. Studies on the functional role of T. W. (1995) Nature (London) 375, 241-244. 52. Bendelac, A., Lantz, O., Quimby, M. E., T will 26. Vidal, S., Tremblay, M. L., Govoni, G., Gau- Yewdell, J. W., Bennink, J. R. & Brut- -y/8 cells provide new insights into thier, S., Sebastiani, G., Malo, D., Skamene, kiewicz, R. R. (1995) Science 268, 863-865. this more extroverted T-cell population E., Olivier, M., Jothy, S. & Gros, P. (1995) 53. Bendelac, A., Killeen, N., Littman, D. R. & (Table 1). J. Exp. Med. 182, 655-666. Schwartz, R. H. (1994) Science 263, 1774- 27. Davis, M. M. & Chien, Y.-H. (1995) Immu- 1778. The excellent secretarial help of Rita Mah- nol. Today 16, 316-318. 54. Emoto, M., Emoto, Y. & Kaufmann, moudi is gratefully acknowledged. I thank Drs. 28. Weintraub, B. C., Jackson, M. R. & S. H. E. (1995) Int. Immunol. 7, 1729-1739. Kirsten Fischer-Lindahl, Jean-Jacques Fourni6, Hedrick, S. M. (1994) J. Immunol. 153, 55. Castano, A. R., Tangri, S., Miller, J. E. W., Craig Morita, Adrian Hayday, and Roger Kur- 3051-3058. Holcombe, H. R., Jackson, M. R., Huse, 29. Kaliyaperumal, A., Falchetto, R., Cox, A., W. D., Kronenberg, M. & Peterson, P. A. lander for providing unpublished data. I thank Dick, R., Shabanowitz, J., Chien, Y.-H., (1995) Science 269, 223-226. Drs. J. Reimann and P. Conradt for helpful Matis, L., Hunt, D. F. & Bluestone, J. A. 56. Pamer, E. G., Wang, C.-R., Flaherty, L., comments. My work is supported by Deutsche (1995) J. Immunol. 155, 2379-2386. Fischer Lindahl, K. & Bevan, M. J. (1992) Forschungsgemeinschaft und Bundesministe- 30. Sciammas, R., Johnson, R. M., Sperling, Cell 70, 215-223. rium fiir Bildung und Forschung. A. I., Brady, W., Linsley, P. S., Spear, P. G., 57. Kurlander, R. J., Shawar, S. M., Brown, Fitch, F. W. & Bluestone, J. A. (1994) J. M. L. & Rich, R. R. (1992) Science 257, 1. Haas, W., Pereira, P. & Tonegawa, S. (1993) Immunol. 152, 5392-5397. 678-679. Annu. Rev. Immunol. 11, 637-685. 31. Porcelli, S., Brenner, M. B., Greenstein, 58. Kaufmann, S. H. E., Rodewald, H. R., Hug, 2. Kronenberg, M. (1994) Curr. Opin. Immu- J. L., Balk, S. P., Terhorst, C. & Bleicher, E. & De Libero, G. (1988) J. Immunol. 140, nol. 6, 64-71. P. A. (1989) Nature (London) 341,447-450. 3173-3179. 3. Sim, G.-K. (1995) Adv. Immunol. 58, 297- 32. Faure, F., Jitsukawa, S., Miossec, C. & Her- 59. O'Brien, R. L., Fu, Y.-X., Cranfill, R., Dal- 343. cend, T. (1990) Eur. J. Immunol. 20, 703- las, A., Ellis, C., Reardon, C., Lang, J., 4. Havran, W. L. & Boismenu, R. (1994) Curr. 706. Carding, S. R., Kubo, R. & Born, W. (1992) Opin. Immunol. 6, 442-446. 33. Mami-Chouaib, F., Miossec, C., Del Porto, Proc. Natl. Acad. Sci. USA 89, 4348-4352. 5. Rock, E. P., Sibbald, P. R., Davis, M. M. & P., Flament, C., Triebel, F. & Hercend, T. 60. Fu, Y.-X., Vollmer, M., Kalataradi, H., Hey- Chien, Y.-H. (1994) J. Exp. Med. 179, 323- (1990) J. Exp. Med. 172, 1071-1082. borne, K., Reardon, C., Miles, C., O'Brien, 328. 34. Kaur, I., Voss, S. D., Gupta, R. S., Schell, R. & Born, W. (1994) J. Immunol. 152, 6. Schild, H., Mavaddat, N., Litzenberger, C., K., Fisch, P. & Sondel, P. M. (1993) J. 1578-1588. Ehrich, E. W., Davis, M. M., Bluestone, Immunol. 150, 2046-2055. 61. Rajasekar, R., Sim, G.-K. & Augustin, A. J. A., Matis, L., Draper, R. K. & Chien, 35. Pfeffer, K., Schoel, B., Gulle, H., Kaufmann, (1990) Proc. Natl. Acad. Sci. USA 87, 1767- Y.-H. (1994) Cell 76, 29-37. S. H. E. & Wagner, H. (1990) Eur. J. Immu- 1771. 7. Herman, A., Kappler, J. W., Marrack, P. & nol. 20, 1175-1179. 62. O'Brien, R. L., Happ, M. P., Dallas, A., Pullen, A. M. (1991)Annu. Rev. Immunol. 9, 36. De Libero, G., Casorati, G., Giachino, C., Palmer, E., Kubo, R. & Born, W. K. (1989) 745-772. Carbonara, C., Migone, N., Matzinger, P. & Cell 57, 667-674. 8. Germain, R. N. (1994) Cell 76, 287-299. Lanzavecchia, A. (1991) J. Exp. Med. 173, 63. Kaufmann, S. H. E. (1990) Immunol. Today 9. Porcelli, S. A. (1995) Adv. Immunol. 59, 1311-1322. 11, 129-136. 1-98. 37. Kabelitz, D., Bender, A., Schondelmaier, S., 64. Ohga, S., Yoshikai, Y., Takeda, Y., Hiro- 10. Moller (1995) Immunol. Rev. 147, 5-108. Schoel, B. & Kaufmann, S. H. E. (1990) J. matsu, K. & Nomoto, K. (1990) Eur. J. 11. E. M. Exp. Med. 171, 667-679. Immunol. 20, 533-538. Beckman, & Brenner, M. B. (1995) 38. Munk, M. E., Gatrill, A. & Kaufmann, 65. Haregewoin, A., Soman, G., Hom, R. C. & Immunol. Today 16, 349-352. S. H. E. (1990) J. Immunol. 145, 2434-2439. Finberg, R. W. (1989) Nature (London) 340, 12. Kozbor, D., Trinchieri, G., Monos, D. S., 39. Behr, C. & Dubois, P. (1992) Int. Immunol. 309-312. Isobe, M., Russo, G., Haney, J. O., Zmijew- 4, 361-366. 66. Kabelitz, D., Bender, A., Prospero, T., Wes- ski, C. & Croce, C. M. (1989) J. Exp. Med. 40. Modlin, R. L., Pirmez, C., Hofmann, F. M., selborg, S., Janssen, 0. & Pechhold, K. 169, 1847-1851. Torigian, V., Uyemura, K., Rea, T. H., (1991) J. Exp. Med. 173, 1331-1338. 13. Holoshitz, J., Koning, F., Coligan, J. E., Bloom, B. R. & Brenner, M. B. (1989) Na- 67. Panchamoorthy, G., McLean, J., Modlin, DeBruyn, J. & Strober, S. (1989) Nature ture (London) 339, 544-548. R. L., Morita, C. T., Ishikawa, S., Brenner, (London) 339, 226-229. 41. Schoel, B., Sprenger, S. & Kaufmann, M. B. & Band, H. (1991) J. Immunol. 147, 14. Matis, L. A., Fry, A. M., Cron, R. Q., Cot- S. H. E. (1994) Eur. J. Immunol. 24, 1886- 3360-3369. terman, M. M., Dick, R. F. & Bluestone, 1892. 68. Ohmen, J. D., Barnes, P. F., Uyemura, K., J. A. (1989) Science 245, 746-749. 42. Tanaka, Y., Sano, S., Nieves, E., De Libero, Lu, S., Grisso, C. L. & Modlin, R. L. (1991) 15. Guo, Y., Ziegler, K., Safley, S. A., Niesel, G., Rosa, D., Modlin, R. L., Brenner, M. B., J. Immunol. 147, 3353-3359. D. W., Vaidya, S. & Klimpel, G. R. (1995) Bloom, B. R. & Morita, C. T. (1994) Proc. 69. Parker, C. M., Groh, V., Band, H., Porcelli, Infect. Immun. 63, 2288-2294. Natl. Acad. Sci. USA 91, 8175-8179. S. A., Morita, C., Fabbi, M., Glass, D., 16. Vidovic, D., Roglic, M., McKune, K., Guer- 43. Constant, P., Davodeau, F., Peyrat, M.-A., Strominger, J. L. & Brenner, M. B. (1990)J. der, S., MacKay, C. & Dembic, Z. (1989) Poquet, Y., Puzo, G., Bonneville, M. & Exp. Med. 171, 1597-1612. Nature (London) 340, 646-650. Fournie, J.-J. (1994) Science 264, 267-270. 70. Miyawaki, T., Kasahara, Y., Taga, K., 17. Imani, F. & Soloski, M. J. (1991) Proc. Natl. 44. Tanaka, Y., Morita, C. T., Nieves, E., Bren- Yachie, A. & Taniguchi, N. (1990) J. Exp. Acad. Sci. USA 88, 10475-10479. ner, M. B. & Bloom, B. R. (1995) Nature Med. 171, 1833-1838. 18. Soloski, M. J., DeCloux, A., Aldrich, C. J. & (London) 375, 155-158. 71. Fisch, P., Malkovsky, M., Kovats, S., Sturm, Forman, J. (1995) Immunol. Rev. 147, 67- 45. Burk, M. R., Mori, L. & De Libero, G. E., Braakman, E., Klein, B. S., Voss, S. D., 90. (1995) Eur. J. Immunol. 25, 2052-2058. Morrissey, L. W., DeMars, R., Welch, W. J., Downloaded by guest on September 26, 2021 Review: Kaufmann Proc. Natl. Acad. Sci. USA 93 (1996) 2279

Bolhuis, R. L. H. & Sondel, P. M. (1990) L., Britta, R., Vaccaro, R. & Bertotto, A. 113. Ladel, C. H., Blum, C., Dreher, A., Reifen- Science 250, 1269-1273. (1992) Immunology 76, 688-670. berg, K. & Kaufmann, S. H. E. (1995) Eur. J. 72. Bukowski, J. F., Morita, C. T., Tanaka, Y., 93. Skeen, M. J. & Ziegler, H. K. (1993) J. Exp. Immunol. 25, 2877-2881. Bloom, B. R., Brenner, M. B. & Band, H. Med. 178, 971-984. 114. Nishimura, H., Emoto, M., Hiromatsu, K., (1995) J. Immunol. 154, 998-1006. 94. van der Heyde, H. C., Elloso, M. M., Yamamoto, S., Matsuura, K., Gomi, H., 73. Tsukaguchi, K., Balaji, K. N. & Boom, Roopenian, D. C., Manning, D. D. & Wei- Ikeda, T., Itohara, S. & Yoshikai, Y. (1995) W. H. (1995) J. Immunol. 154, 1786-1796. danz, W. P. (1993) Eur. J. Immunol. 23, Eur. J. Immunol. 25, 1465-1468. 74. Barnes, P. F., Grisso, C. L., Abrams, J. S., 1846-1850. 115. Weiner, H. L., Friedman, A., Miller, A., Band, H., Rea, T. H. & Modelin, R. L. 95. van der Heyde, H. C., Elloso, M. M., Chang, Khoury, S. J., Al-Sabbagh, A., Santos, L., (1992) J. Infect. Dis. 165, 506-512. W.-L., Kaplan, M., Manning, D. D. & Wei- Sayegh, M., Nussenblatt, R. B., Trentham, 75. Follows, G. A., Munk, M. E., Gatrill, A. J., danz, W. P. (1995) J. Immunol. 154, 3985- D. E. & Hafler, D. A. (1994) Annu. Rev. Conradt, P. & Kaufmann, S. H. E. (1992) 3990. Immunol. 12, 809-880. Infect. Immun. 60, 1229-1231. 96. Perera, M. K., Carter, R., Goonewardene, 116. Fujihashi, K., Taguchi, T., Aicher, W. K., 76. Ferrick, D. A., Schrenzel, M. D., Mulvania, R. & Mendis, K. N. (1994)1. Exp. Med. 179, McGhee, J. R., Bluestone, J. A., Eldridge, T., Hsieh, B., Ferlin, W. G. & Lepper, H. 311-315. J. H. & Kiyono, H. (1992) J. Exp. Med. 175, (1995) Nature (London) 373, 255-257. 97. Janeway, C. A., Jones, B., Jr., & Hayday, A. 695-707. 77. Skeen, M. J. & Ziegler, H. K. (1995) J. Im- (1988) Immunol. Today 9, 73-76. 117. Yamamoto, M., Fujihashi, K., Beagley, munol. 154, 5832-5841. K. W., McGhee, J. R. & Kiyono, H. (1993) 78. Subauste, C. S., Chung, J. Y., Do, D., Ko- 98. Rosat, J.-P., MacDonald, H. R. & Louis, J. A. (1993) J. Immunol. 150, 550-555. J. Immunol. 150,106-114. niaris, A. H., Hunter, C. A., Montoya, J. G., 118. McMenamin, C., McKersey, M., Kuhnlein, Porcelli, S. & Remington, J. S. (1995)J. Clin. 99. Fu, Y.-X., Roark, C. E., Kelly, K., Drevets, D., Campbell, P., O'Brien, R. & Born, W. P., Hunig, T. & Holt, P. G. (1995) J. Immu- Invest. 96, 610-619. nol. 154, 4390-4394. 79. Lang, F., Peyrat, M. A., Constant, P., (1994) J. Immunol. 153, 3101-3115. 100. Hisaeda, H., Nagasawa, H., Maeda, K-i., 119. McMenamin, C., Pimm, C., McKersey, M. & Davodeau, F., David-Ameline, J., Poquet, Holt, P. G. (1994) Science 265, 1869-1871. Y., Vie, H., Fournie, J. J. & Bonneville, M. Maekawa, Y., Ishikawa, H., Ito, Y., Good, R. A. & Himeno, K. (1995)J. Immunol. 154, 120. Kaufmann, S. H. E., Blum, C. & Yamamoto, (1995) J. Immunol. 154, 5986-5994. S. (1993) Proc. Natl. Acad. Sci. USA 90, 80. Kaufmann, S. H. E. (1993) Annu. Rev. Im- 244-251. 101. Itohara, S., Mombaerts, P., Lafaille, J., Ia- 9620-9624. munol. 11, 129-163. 121. Viney, J. L., Dianda, L., Roberts, S. J., Wen, 81. Janis, E. M., Kaufmann, S. H. E., Schwartz, comini, J., Nelson, A., Clarke, A. R., Hooper, M. L., Farr, A. & Tonegawa, S. L., Mallick, C. A., Hayday, A. C. & Owen, R. H. & Pardoll, A. M. (1989) Science 244, M. J. (1994) Proc. Natl. Acad. Sci. 91, 713-717. (1993) Cell 72, 337-348. 11948-1 1952. 82. Augustin, A., Kubo, R. T. & Sim, G.-K. 102. Mombaerts, P., Clarke, A. R., Rudnicki, 122. Poussier, P. & Julius, M. (1994) Annu. Rev. (1989) Nature (London) 340, 239-241. M. A., Iacomini, J., Itohara, S., Lafaille, Immunol. 12, 521-553. 83. Russo, D. M., Armitage, R. J., Barral- J. J., Wang, L., Ichikawa, Y., Jaenisch, R., 123. Havran, W. L., Chien, Y.-H. & Allison, J. P. Netto, M., Barral, A., Grabstein, K. H. & Hooper, M. L. & Tonegawa, S. (1992) Na- 3712- (1991) Science 252, 1430-1432. Reed, S. G. (1993) J. ImmunoL 151, ture (London) 360, 225-231. 124. Boismenu, R. & Havran, W. L. (1994) Sci- 3718. 103. Tsuji, M., Mombaerts, P., Lefranqois, L., 84. Flenghi, L., Pileri, S., Pelicci, P., ence 266, 1253-1255. Falini, B., Nussenzweig, R. S., Zavala, F. & Tonegawa, 125. Cepek, K. L., Shaw, S. K., Parker, C. M., Fagioli, M., Martelli, M. F., Moretta, L. & S. (1994) Proc. Natl. Acad. Sci. USA 91, Ciccone, E. (1989) J. Immunol. 143, 2480- Russell, G. J., Morrow, J. S., Rimm, D. L. & 345-349. Brenner, M. B. (1994) Nature (London) 372, 2488. 104. Langhorne, J., Mombaerts, P. & Tonegawa, 85. Inoue, T., Yoshikai, Y., Matsuzaki, G. & 190-193. S. (1995) Int. Immunol. 7, 1005-1011. 126. L., Barrett, T. A., Havran, W. L. Nomoto, K. (1991) J. Immunol. 146, 2754- 105. Ladel, C. H., Hess, J., Daugelat, S., Mom- Lefranqois, 2762. & Puddington, L. (1994) Eur. J. Immunol. baerts, P., Tonegawa, S. & Kaufmann, 24, 635-640. 86. Sandor, M., Sperling, A. I., Cook, G. A., S. H. E. (1995) Eur. J. Immunol. 25, 838- Weinstock, J. V., Lynch, R. G. & Bluestone, 127. Komano, H., Fujiura, Y., Kawaguchi, M., 846. Matsumoto, S., Hashimoto, Y., Obana, S., J. A. (1995) J. Immunol. 155, 275-284. 106. Kaufmann, S. H. E. & Ladel, C. H. (1994) 87. Balbi, B., Valle, M. T., Oddera, S., Giunti, Mombaerts, P., Tonegawa, S., Yamamoto, Trends Microbiol. 2, 235-242. H., Itohara, S., Nanno, M. & Ishikawa, H. D., Manca, F., Rossi, G. A. & Allegra, L. 107. D., Pakpreo, P., Filla, J., Pederson, (1993)Am. Rev. Respir. Dis. 148,1685-1690. Muller, (1995) Proc. Natl. Acad. Sci. USA 92, 6147- 88. Emoto, M., Nishimura, H., Sakai, T., Hiro- K., Cigel, F. & Malkovska, V. (1995) Infect. 6151. matsu, K., Gomi, H., Itohara, S. & Yoshikai, Immun. 63, 2361-2366. 128. Halstensen, T. S., Scott, H. & Brandtzaeg, Y. (1995) Infect. Immun. 63, 3736-3738. 108. Roberts, A. D., Ordway, D. J. & Orme, I. M. P. (1989) Scand. J. Immunol. 30, 665-672. 89. Bertotto, A., Gerli, R., Spinozzi, F., Muscat, (1993) Infect. Immun. 61, 1113-1116. 129. Bloom, B. R. & Murray, C. J. L. (1992) Sci- C., Scalise, F., Castellucci, G., Sposito, M., 109. Galea, P., Brezinschek, R., Lipsky, P. E. & ence 257, 1055-1064. Candio, F. & Vaccaro, R. (1993) Eur. J. Oppenheimer-Marks, N. (1994)J. Immunol. 130. Kaufmann, S. H. E. & Van Embden, Immunol. 23, 1177-1180. 153, 529-542. J. D. A. (1993) Trends Microbiol. 1, 2-5. 90. Hara, T., Mizuno, Y., Takaki, K., Takada, 110. Jones-Carson, J., Vazquez-Torres, A., van 131. Crowle, A. J. (1988) Infect. Immun. 56, H., Akeda, H., Aoki, T., Nagata, M., Ueda, der Heyde, H. C., Warner, T., Wagner, 2769-2773. K., Matsuzaki, G., Yoshikai, Y. & Nomoto, R. D. & Balish, E. (1995) Nat. Med. 1, 132. Strominger, J. L. (1989) Cell 57, 895-898. K. (1992) J. Clin. Invest. 90, 204-210. 552-557. 133. Heilig, J. S. & Tonegawa, S. (1987) Proc. 91. Sumida, T., Maeda, T., Takahashi, H., Yo- 111. Mixter, P. F., Camerini, V., Stone, B. J., Natl. Acad. Sci. USA 84, 8070-8074. shida, S., Yonaha, F., Sakamoto, A., To- Miller, V. L. & Kronenberg, M. (1994) In- 134. Garman, R. D., Doherty, P. J. & Raulet, mioka, H. & Koike, T. (1992) Infect. Immun. fect. Immun. 62, 4618-4621. D. H. (1986) Cell 45, 733-742. 60, 2554-2558. 112. Yamamoto, S., Russ, F., Teixeira, H. C., 135. Asarnow, D. M., Kuziel, W. A., Bonyhadi, 92. Scalise, F., Gerli, R., Castellucci, G., Spi- Conradt, P. & Kaufmann, S. H. E. (1993) M., Tigellar, R. R., Tucker, P. W. & Allison, nozzi, F., Fabietti, G. M., Crupi, S., Sensi, Infect. Immun. 61, 2154-2161. J. P. (1988) Cell 55, 837-847. Downloaded by guest on September 26, 2021