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

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