DOCSLIB.ORG

LETTERS to NATURE Lymphocytes Bearing Antigen- Specific Yo T -Cell

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
LETTERS to NATURE Lymphocytes Bearing Antigen- Specific Yo T -Cell LETTERS TO NATURE 24 25 clonal anergy observed in B cells • • It is likely that our findings and immunological functions of these T cells remains enigmatic. will contribute to better understanding of the obviously complex We report here that in contrast to the normal low frequency of mechanisms involved in the induction of unresponsiveness in yB-bearing cells in lymphoid tissues, peripheral blood, or normal the mature immune system. D skin, the frequency is increased five to eightfold in particular granulomatous reactions of leprosy. TCR yfi+ lymphocyte lines from these leprosy skin lesions proliferate in vitro specifically to Received 14 February; accepted 14 April 1989. mycobacterial antigens. This reactivity to foreign antigens appears 1. Kappler. J. W .. Roehm, N. & Marrack. P. Cell 49, 273-280 (1987). to require presentation in the context of self-molecules. Moreover, 2. Kappler, J. W. Staerz. U.. White, J. & Marrack, P. C. Nature 332, 35-40 (1988). 3. MacDonald. H. R. et a/. Nature 40-45 (1988). culture supernatants from activated yfi T lymphocytes induce 4. Kisielow. P.. BIUthmann. H.. Staerz. U. D., Steinmetz. M & von Boehmer, H. Nature 333,742-746 adhesion and aggregation of bone-marrow monocytes in the (1988) 5. Jacobson, J.. Ullieh66k, B. & Blomgren. H. Scand. J. lmmun. 4, 181-191 (1975). presence of granulocyte monocyte-colony stimulating factor 6. Ulliehook, B .. Jacobson, H. & Blomgren. H. Scand. J. lmmun. 4, 209-216 (1975). (CSF), suggesting that products of yB-bearing T cells may play 7. Miller. S. D.. Sy, M.-S. & Claman. H. N. Eur. J. lmmunol 7, 165-170 (1977). 8. Brondz, B. D .. Karanlov, A. V, Abronina,l. F. & Blandova. L. K. Scand J. lmmun.13, 517-534 (1981). a role in the immune response, possibly by stimulating granuloma 9. Jenkins. M K. & Schwartz. R. H. J. exp. Med 165, 302-319 (1987). formation. 10 von Boehmer, H. Teh. H. S. & Kisielow. P lmmun. Today 10, 57-61 (1989). Leprosy comprises a varied clinical spectrum that parallels 11. Markmann, J. eta/. Nature 336, 476-479 (1988). 12. Lamb, J. R. eta/. J. exp. Med. 157, 1434-1447 (1983). cell-mediated immunity, the skin lesions of which are readily 13. Lamb, J. R. & Feldmann. M. Nature 306, 72-74 (1984). accessible for studl. Tuberculoid leprosy lesions contain rela­ 14. Quill, H. & Schwartz, R. H. J. /mmun. 138, 3704-3712 (1987). 15. Jenkins, M. K., Pardoll. D. M., Mizuguchi, J., Chused, T. M. & Schwartz. R. H. Proc. natn. Acad. Sci. tively few organisms, and the host mounts a strong cell-mediated US.A. 84, 5409-5413 (1987). immune response which restricts growth of the bacilli. In 16. Festenstein, H. Transplantn Rev. 15, 62-88 (19731. 17. Abe. R. & Hodes. R. J. lmmun. Today 9, 230-235 (1988). lepromatous leprosy, however, numerous skin lesions are found 18. Halle-Pannenko. 0 .. Pntchard, L. L. & Bruley-Rosse!, M. Eur. J. lmmun. 17, 1751-1755 (1987). containing high numbers of acid fast bacilli, and the host exhibits 19. von Boehmer. H. & Schubrger. K. Eur J. lmmun. 14, 1048-1052 (1984). 7 unresponsiveness to Mycobacterium leprae antigens • Superim­ 20. Ready, A. R.. Jenkinson. E. J.. Kingston. R. & Owen. J. J. I. Nature 310, 231-233 (1984). 21. Flajnik, M. F., DuPasqurer. L. & Cohen, N. Eur. J. lmmun. 15, 540-547 (1985). posed on this spectrum are reactional states including reversal 22. Ohki. H., Martin, C., Corbel, C .. Colley, M. & Le Douarin. N. M. Science 237, 1032-1035 (1987). reactions and lepromin skin tests. Reversal reactions appear to 23. Marrack. P. eta/. Cell 53, 627-634 (1988) 24. Nossal. G. J. V. & Pike, B. L. Proc. natn Acad Sci. US.A. 77, 1602-1606 (1980). be acute delayed-type hypersensitivity reactions characterized 25. Goodnow. C. C. eta/. Nature 334, 676-682 (1988). by erythematous tumid lesions containing organized granulomas 26. Janeway, C. A .. Jr .. Fischer-Undahl. K. & Hammerling, U. lmmun. Today 9, 125-126 (1988). 8 in which CD4+ T cells predominate . Patients with tuberculoid 27. Payne, J. et a/. Proc. natn. Acad. Sci. US.A. 85, 7695-7698 (1988). 28. Dialynas, D. P. eta/. J. lmmun. 131, 2445-2451 (1983). leprosy and reversal reactions manifest positive lepromin skin 29. Malek. T. R., Robb, R. J. & Shevach. E. M. Proc. natn. Acad. Sci USA. 80, 5694-5698 (1983). tests (Mitsuda reactions) which are organized granulomatous 30. Ceredig, R.. Lowenthal. J. W .. Nabholz. M. & MacDonald, H. R. Nature 314, 98-100 (1985). 9 reactions to M. leprae of three to four weeks duration . ACKNOWLEDGEMENTS. We thank Jan Klein for his continuous support, Hans Hengartner for providing We compared the occurrence of lymphocytes bearing TCR yo the 44-22-1 hybridoma, Stefan Faath for technical assistance, and Lynne Yakes for preparing the manuscript. Th1s work was supported in part by Sonderforschungsbereich No. 120 or TCR af3 in each of these immunological reactions to M. leprae using immunoperoxidase staining of skin biopsy speci­ mens with specific monoclonal antibodies. TCR af3+ lym­ phocytes across the disease spectrum and in each of these reactional states were detected by staining with monoclonal Lymphocytes bearing antigen­ antibody {3F1 (ref. 10) (reacts with shared determinants present on all human TCR f3 chains), whereas TCR yo+ T cells were specific yo T-cell receptors detected by staining with monoclonal antibody anti-TCRo 1 (ref. accumulate in human 11) (reacts with shared determinants present on all human TCR o chains). In both lepromin skin tests and in reversal reactions, infectious disease lesions TCRo1 + lymphocytes comprised 25-35 per cent of CD3+ cells in the lesions compared to -5 per cent of the CD3+ cells in Robert. L. Modlin*t, Claude Pirmezt, lesions of other forms of the spectrum (Figs 1 and 2) or in Florence M. Hofmant, Victoria Torigian*t, normal lymphoid organs. This suggests that TCR yo lym­ phocytes may be involved in early active granulomatous Koichi Uyemurat, Thomas H. Rea*, responses (such as lepromin skin tests and reversal reactions), Barry R. Bloom+ & Michael B. Brenner§ in contrast to the more chronic and/ or immunologically un­ responsive leprosy lesions. * Section of Dermatology, and t Department of Pathology, Localized American cutaneous leishmaniasis is another in­ University of Southern California School of Medicine, Los Angeles, 12 fectious disease with granulomatous skin reactions • We found California 90033, USA similarly that TCR yo+ cells also were present in large numbers t Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA in these lesions. Twenty per cent of the CD3+ cells in such §Laboratory of Immunochemistry, Dana-Farber Cancer Institute and lesions stained with anti-TCRo1, corresponding to a sevenfold Department of Rheumatology and Immunology, Brigham and Women's increase over the percentage of these lymphocytes in peripheral Hospital. Harvard Medical School, Boston, Massachusetts 02115, USA blood from the same patients, or in Montenegro skin reactions ( 48 h delayed type hypersensitivity responses to leishmania anti­ THE majority ofT cells bear the T -cell receptor (TCR) ap complex gen) or in mucocutaneous leishmaniasis (a chronic destructive which recognizes foreign antigen peptides only in the context of form of the disease) where typically only 5% of the CD3+ cells 1 self major histocompatibility complex (MHC) molecules • Such express a TCR o chain (Figs 1 and 2). T cells function in a variety of effector roles and secrete cytokines The specific recognition of antigens by TCR yo lymphocytes that mediate the activation and differentiation of other cells in the has been difficult to demonstrate. These lymphocytes have been 13 14 15 immune system. Recently, a small subpopulation T cells was found noted to lyse tumour cells ' as well as allogeneic target cells . 2 to bear a distinct TCR composed of y and B subunits • In man, But evidence for y8 T cells with specificity for soluble antigens TCR yfi+ cells are distributed as -5 per cent of the CD3+ cells or exhibiting self-restricted recognition of foreign antigens has in all organized lymphoid organs as well as in the skin- and been lacking. To examine the antigen specificity of lymphocytes 3 gut-associated lymphoid tissues • Although a limited number of accumulated in leprosy lesions, we derived T-cell lines from germ-line genes encode the TCR y and B subunits, extensive skin lesions and peripheral blood as previously described (Fig. junctional variation particularly in the B gene, results in unpre­ 3; see ref. 16). One T-cellline was obtained from the biopsy of 4 5 cedented diversity for this receptor ' The nature of the specificity a lepromin skin test of a patient with tuberculoid leprosy in 544 NATURE · VOL 339 · 15 JUNE 1989 © 1989 Nature Publishing Group LETTERS TO NATURE reversal reaction. This line was expanded in vitro with M. leprae were unequivocally higher than control stimulations using the antigens and with interleukin-2 (11-2), and then was subjected same culture conditions except for medium lacking in these to cell sorting to isolate lymphocytes unreactive with monoclonal antigens (256 c.p.m.). antibodies against TCR a/3 (WT31) and CD4 (which is rarely Because the TCR a/3 complex recognizes antigens in the expressed on TCR y8+ cells). The resulting cell line was enriched context of self-MHC molecules, it was of interest to ask whether for y8 T cells (99% TCR81 +and 1% WT31 +).This line prolifer­ antigen recognition by TCR y8 cells requires self antigen pres­ ates specifically in response to M. leprae cell-wall antigens entation. Experiments using antigen-presenting cells (APCs) of (15,256 c. p.m.) and tuberculin purified protein derivative (PPD) differing HLA types revealed that the TCR y8 lymphocytes (27 ,478 c. p.m.) but not to the 65K (relative molecular mass) appear to require self or matched antigen-presenting cells.
Load more

Recommended publications
  • Is the H-2K Locus of the Mouse Stronger Than the H-2D Locus?
    Tissue Antigens (1972), 2, 262-266 Published by Munksgaard, Copenhagen, Denmark No part may be reproduced by any process without written permission from the author(s) Is the H-2K Locus of the Mouse Stronger Than the H-2D Locus? JAN KLEIN Department of Oral Biology, School of Dentistry, Department of Human Genetics, Medical School, The University of Michigan, Ann Arbor, Michigan 48104 Rrceived for publication 23 February, ncceptcd 4 Apiil 1972 Recently, evidence has been gathered dence for the “superiority of the K-end in- showing that the H-2 complex of tlic compatibilities over the D-end incompati- mouse consists of only two histocompati- bilities” (RychlikovA et al. 1971). In this bility genes (regions), H-2K and H-2D communication, evidence is presented that : (Klein & Shreffler 1972). The rest of the 1) skin graft rejection does occur across H-2 regions described in the literature the H-2D barrier, and 2) H-2K, at least (C,V,E,A) are probably serological arti- in the combinations studied, presents a facts. Kychlikovi and co-workers ( 197 1) stronger histocompatibility barrier than reported that significant transformation of H-2D. allogeneic lymphocytes in mixed cultures Four intra-H-2 crossovers (Table I ) , (MLC) occurred when congenic strain two proven (i.e. H-2h-3Sg,H-2i-2Sg) and combinations differed at the H-2I< locus two suspected 1i.e. H-2a,H-2m), and four and did not occur when the combinations H-2 chromosomes from which the cross- differed at the H-2D locus. According to overs were derived ( H-2b,H-2d,H-2k,H- Dkmant ( 1970), a similar phenomenon 24), were arranged in eight different do- can be observed in the graft-versus-host nor-recipient combinations (Table 11).
    [Show full text]
  • Evolution of Mouse Major Histocompatibility Complex Genes Borne by T Chromosomes (Class II Genes/T Complex/Restriction Fragments/Polymorphism)
    Proc. Natl. Acad. Sci. USA Vol. 82, pp. 2819-2823, May 1985 Evolution Evolution of mouse major histocompatibility complex genes borne by t chromosomes (class II genes/t complex/restriction fragments/polymorphism) FELIPE FIGUEROA, MLADEN GOLUBI(*, DEAN NIETI(*, AND JAN KLEIN Max-Planck-Institut fur Biologie, Abteilung Immungenetik, Corrensstrasse 42, 7400 Tubingen, Federal Republic of Germany Communicated by Ray D. Owen, December 26, 1984 ABSTRACT Virtually all wild mouse populations carry t H-2 genes are highly polymorphic and hence can be used to haplotypes that cause embryonic lethality or semilethality, differentiate chromosomes (8). On the t chromosomes, the distortion of segregation ratios, suppression of crossing-over, H-2 complex is included in the region of suppressed cross- and male sterility. The t complex of genes is located on ing-over and it is therefore ideally suited for tracing the origin chromosome 17, closely linked to the H-2, the major histocom- of t haplotypes. In a previous study, we used serology of the patibility complex of the mouse. The t haplotypes differ from H-2 antigens as a tool to determine the degree of relatedness each other not only in lethal genes they carry but also in their among the different t haplotypes (9, 10). In this report, we linked H-2 haplotypes. In this study, we compared the class II applied the genomic Southern blot hybridization technique to H-2 genes present on 31 t chromosomes extracted from wild the class II genes of the H-2 complex carried by the different populations in different parts ofthe world.
    [Show full text]
  • Klein J. Biology of the Mouse Histocompatibility-2 Complex: Principles of Immunogenetics Applied to a Single System
    ® CC/NUMBER 20 This Week’s Citation Classic MAY 16,1988 Klein J. Biology of the mouse histocompatibility-2 complex: principles of immunogenetics applied to a single system. New York: Springer-Verlag, 1975. 620 p. [Department of Microbiology, University of Texas Southwestern Medical School. Dallas, TXI True to its name, the major histocompatibility com- fore decided to review the literature system- plex (Mhc) is one of the most intricate genetic sys- atically, to organize it, and to try to make some tems known. When it became known in 1974 that sense out of it. Mhc codes for one of three principal immunological At first I thought a paper of some 70 pages molecules, many immunologists began using this or so would suffice, and I made arrangements book as a guide through the maze of esoteric symbols with the editors of Series Haematologica to and knowledge scattered in a large variety of journals. publish the overview as one of their issues. I It is perhaps not an exaggeration to say that the book soon realized, however, that the work would reared a generation of immunologists. [The SCI~in- be much longer. I then started to look for a dicates that this book has been cited in over 1375 publisher willing to bring the manuscript out publications.1 in the form of a book. At a conference at the Asilomar Conference Center, Monterey, California, I met Dietrich Gölze, who was then a postdoctoral fellow at the Scripps Clinic working on the 11-2 complex, which is the Jan Klein mouse version of Mhc and the epitome of all Abteilung lmmungenetik such complexes.
    [Show full text]
  • Prototypic T Cell Receptor and CD4-Like Coreceptor Are Expressed by Lymphocytes in the Agnathan Sea Lamprey
    Prototypic T cell receptor and CD4-like coreceptor are expressed by lymphocytes in the agnathan sea lamprey Zeev Pancer*, Werner E. Mayer†, Jan Klein‡, and Max D. Cooper*§¶ *Departments of Medicine, Pediatrics, and Microbiology, Division of Developmental and Clinical Immunology, and §Howard Hughes Medical Institute, University of Alabama at Birmingham, Birmingham, AL 35294; †Max-Planck-Institut fu¨r Entwicklungsbiologie, Abteilung fu¨r Evolutionsbiologie, Spemannstrasse 37-39, D-72076 Tu¨bingen, Germany; and ‡Department of Biology, Pennsylvania State University, 208 Mueller Laboratory, University Park, PA 16802-5301 Contributed by Max D. Cooper, July 29, 2004 All jawed vertebrates have highly diverse lymphocyte receptors, jawed vertebrates and the best available candidates in which to which allow discrimination between self and nonself antigens as search for the molecular and cellular precursors of the combi- well as the recognition of potential pathogens. Key elements of the natorial AIS. anticipatory recombinatorial immune system in jawed vertebrates The lamprey hematopoietic tissues and blood stream abound are the TCR, Ig, and MHC genes, but their ancestral genes have not with cells resembling mammalian lymphocytes (11–15). These been found in more basal vertebrates. In this study, we extended cells can undergo lymphoblastic transformation and prolifera- our analysis of the transcriptome of lymphocyte-like cells in the tion in response to stimulation with antigens and plant mitogens lamprey to identify the TCR-like and CD4-like genes. The structural (16), and they have been implicated as key cellular elements in features of these genes and their preferential expression in lym- adaptive immune responses that have been reported for these phocytes make them attractive candidates for ancestral TCR and jawless vertebrates (17), including rejection of second-set skin CD4 genes.
    [Show full text]
  • Associated Histocompatibility Region in the H-2 Complex of the Mouse
    Immunogenetics 1:45 - 56, 1974 by Springer-Verlag New York Inc. 1974 Evidence for a Third,/r-Associated Histocompatibility Region in the H-2 Complex of the Mouse Jan Klein,1,2 Miroslav Hauptfeld,/ and V~ra Hauptfeld2 1Department of Oral Biology, School of Dentistry 2Department of Human Genetics, Medical School The University of Michigan, Ann Arbor, Michigan 48104 Abstract Skin grafts transplanted from B 10.HTT donors onto (A.TL X B 10)F 1 recipients are rapidly rejected despite the fact that the B10.HTT and A.TL strains should be carrying the same H-2 chromosomes and that both the donor and the recipient contain the B10 genome. The rejection is accompanied by a production of cytotoxic antibodies against antigens controlled by the Ir region of the H-2 complex. These unexpected findings are interpreted as evidence for a third histocompatibility locus in the H~ complex, H-2I, located in the Ir region close to H-2K. The B 10.HTT and A.TL strains are postulated to differ at this hypothetical locus, and the difference between the two strains is explained as resulting from a crossing over between the H-2 tl and H-2 s chromosomes in the early history of the B10.HTT strain. The H-2 geno- types of the B10.HTT and A.TL strains are assumed to be H-2KsIrs/kSskH-2D d and H-2KsIrkSskH-2D d, respectively. Thus, the H-2 chromosomes of the two strains differ only in a portion of the Ir region, including the H-2I locus.
    [Show full text]
  • 091400 the HLA System — Second of Two Parts
    The New England Journal of Medicine Review Articles Advances in Immunology ABNORMALITIES OF GENES LINKED TO THE HLA COMPLEX A large group of diseases involve genes in the HLA I AN MACKAY, M.D., AND FRED S. ROSEN, M.D., Editors region that are linked to (or associated with) specific class I and class II alleles or combinations of alleles (haplotypes). In some of these diseases, the responsi- THE HLA SYSTEM ble genes are unrelated to the class I and class II genes, but in other diseases, the class I and class II genes are involved. Second of Two Parts Narcolepsy JAN KLEIN, PH.D., AND AKIE SATO, PH.D. Narcolepsy is a debilitating neurologic condition characterized by excessive daytime sleepiness and sud- den, uncontrollable periods of sleep. The disease is DEFICIENCIES OF HLA MOLECULES caused by a defect in the gene coding for the hypo- A clinician’s attention is normally drawn to a sys- cretin type 2 receptor (HCRTR2).30,31 Hypocretins tem only when it malfunctions. The HLA system is (orexins) are neuropeptides expressed by a small clus- no exception in this regard, but in contrast to other ter of neurons in the lateral hypothalamus. To act, systems, it also arouses interest when it functions hypocretins must bind to receptors, one of which well — too well, in fact. The most dramatic malfunc- is rendered nonfunctional by a mutation carried by tion of the HLA system occurs when its genes falter patients with narcolepsy. The mutation apparently in their expression, resulting in HLA class I or class arose in a common ancestor of these patients, in the II deficiencies (the bare lymphocyte syndrome, in HCRTR2 gene located in the vicinity of the HLA- which “bare” refers to the low level of HLA mole- DQB1*0602 and DQA1*0102 alleles.
    [Show full text]
  • Position of the Translocation Break T(2;9
    Genet. Res., Camb. (1972), 19, pp. 177-179 177 Printed in Great Britain Position of the translocation break T{2; 9)138Ca in linkage group IX of the mouse BY JAN KLEIN AND DAGMAB, KLEIN Department of Oral Biology, School of Dentistry, and Department of Human Genetics, School of Medicine, The University of Michigan, Ann Arbor, Michigan 48104, U.S.A. {Received 29 June 1971) SUMMARY The translocation break T(2;9)138Ca is located about three map units from the H-2 region on the non-centromeric side of the IXth linkage group. The recombination frequency in the T-H-2 interval is increased in the presence of the T138 translocation to about twice its value in the absence of the translocation. 1. INTRODUCTION The H-2 system is one of the most studied loci in the mouse. It is located in the IXth linkage group (Gorer, Lyman & Snell, 1948), some 14 map units from the centromere (Klein, 1971). In the same linkage group are also genes T(t), qk, tf, Fu, Ki and Low (see Green (1966), for references). All of these loci have been mapped on one side (the centromeric side) of the H-2 complex. The only gene known to be located on the non- centromeric side oiH-2 is Tla (thymus leukemia antigen which determines the presence or absence of the TL antigen in the thymus and leukemias) (Boyse & Old, 1969). For genetic studies of the H-2 complex requiring flunking markers on both sides of the com- plex, the Tla locus is of limited value.
    [Show full text]
  • IB Region in the H-2 Complex
    Proc. Nati Acad. Sci. USA Vol. 78, No. 6, pp. 3809-3813, June 1981 Immunology A novel type of T-T cell interaction removes the requirement for I-B region in the H-2 complex (Ia antigens/Ir genes/T-cell proliferation/suppression) CONSTANTIN N. BAXEVANIS, ZOLTAN A. NAGY, AND JAN KLEIN* Max-Planck-Institut fir Biologie, Abteilung Immungenetik, 7400 Tuibingen, Federal Republic of Germany Communicated by George Klein, February 26, 1981 ABSTRACT When tested in the in vitro T-cell proliferation MATERIALS AND METHODS assay, H-2a cells are nonresponders to lactate dehydrogenase B (LDH-B; L-lactate:NAD' oxidoreductase, EC 1.1.1.27) and to IgG2a myeloma protein. However, the cells can be converted into Mice. Mice were obtained from our colony at the Max- responders either by the addition to the culture ofmonoclonal anti- Planck-Institute for Biology. The strains and their alleles at H- Ia.m7 antibody or by the removal from the culture of Lyt-2+ [T- 2 regions are given in Table 1. lymphocyte-associated alloantigen (Lyt)-2 positive] lymphocytes. Antigens. The ammonium sulphate precipitate of LDH-B4 In both instances, the responsiveness can be suppressed again by (Boehringer Mannheim) was extensively dialyzed against cul- the addition to the culture of monoclonal antibodies to I region- ture medium and stored at 4°C. Purified IgG2a myeloma pro- associated (Ia) molecules controlled by the I-A subregion. These teins UPC10 and RPC5 were obtained from Bionetics (Frank- data suggest that, in some H-2 haplotypes, the response to LDH- furt, Federal Republic of Germany) and stored at -70°C.
    [Show full text]
  • Brief Detinitive Report
    Brief Detinitive Report RESTRICTION MOLECULES INVOLVED IN THE INTERACTION OF T CELLS WITH ALLOGENEIC ANTIGEN-PRESENTING CELLS* BY NORIHISA ISHII,:~ ZOLTAN A. NAGY, AND JAN KLEIN From the Max Planck Institut ffi'r Biologic, Abteilung Immungenetik, 7400 Tubingen, Federal Republic of Germany T cells stimulated by a soluble antigen in vivo and restimulated in vitro respond to the stimulus by proliferation, provided that the stimulating and restimulating antigen- presenting cells (APC) share molecules controlled by the major histocompatibility complex (MHC) (1). The response of T cells to an antigen is thus restricted by the MHC molecules of the APC (in the mouse, the A~A~ or A and E,,E~ or E molecules controlled by the H-2 complex) (2-5). The interaction of syngeneic T cells and APC is subject to two constraints. First, certain combinations of antigen and MHC molecules are not recognized by T cells, and this nonrecognition constitutes the basis for the identification of MHC-associated immune response (It) genes. Second, in strains carrying responder haplotypes (i.e., strains in which a given combination of MHC molecules and antigen is recognized by T cells), the MHC context of antigen recognition is remarkably constant. Thus, some antigens, such as poly(Glu4°Ala% (GA) and lactate dehydrogenase B (LDHB), are recognized by all responder strains in the context of the A molecule, whereas others, such as poly(Glu 51, Lys ~, Tyr 15) (GLT), are recognized (with the exception of two H-2 haplotypes) in the context of the E molecule (5, 6). We have recently demonstrated that the first constraint does not operate when the T cells and the APC are allogeneic: not only are antigen-pulsed APC able to stimulate allogeneic T cells, but the stimulation occurs regardless of whether the T cell-APC combination is of the R-R, R-NR, NR-R, or NR-NR type (where R and NR are responder and nonresponder MHC haplotypes, respectively, of T cells and APC) (7-9).
    [Show full text]
  • Evolutionary Redefinition of Immunoglobulin Light Chain Isotypes in Tetrapods Using Molecular Markers
    Evolutionary redefinition of immunoglobulin light chain isotypes in tetrapods using molecular markers Sabyasachi Das1, Nikolas Nikolaidis2, Jan Klein, and Masatoshi Nei1 Institute of Molecular Evolutionary Genetics and Department of Biology, Pennsylvania State University, University Park, PA 16802 Contributed by Masatoshi Nei, September 4, 2008 (sent for review July 24, 2008) The phylogenetic relationships of Ig light chain (IGL) genes are ␬ and ␭ denominations had been extended from human to other difficult to resolve, because these genes are short and evolve species, including the rabbit, which cannot be assumed to possess relatively fast. Here, we classify the IGL sequences from 12 tetra- the distinguishing antigenic determinants because otherwise it pod species into three distinct groups (␬, ␭, and ␴ isotypes) using would not recognize them as foreign. Initially, when only a small conserved amino acid residues, recombination signal sequences, number of human IGLV proteins were examined, the groupings and genomic organization of IGL genes as cladistic markers. From established by serologic typing and by sequencing were congru- the distribution of the markers we conclude that the earliest extant ent. Later, however, when a large number of IGLV sequences ␬ ␭ ␴ tetrapods, the amphibians, possess three IGL isotypes: , , and . had been accumulated, the sequence-based phylogenetic trees ␬ ␭ Of these, two ( and ) are also found in reptiles and some often failed to distinguish clearly the expected two groups. This ␭ mammals. The isotype is found in all tetrapods tested to date, finding signaled that difficulties could be expected in an exten- ␬ whereas the isotype seems to have been lost at least in some sion of this kind of phylogenetic analysis to other species.
    [Show full text]
  • The HLA System
    The New England Journal of Medicine Review Articles Advances in Immunology plasmic tail (Fig. 2). There are some 20 class I genes in the HLA region; three of these, HLA-A, B, and C, the so-called classic, or class Ia genes, are the main I AN MACKAY, M.D., AND FRED S. ROSEN, M.D., actors in the immunologic theater. Editors The class II genes code for the a and b polypeptide chains of the class II molecules (Fig. 2). The desig- nation of their loci on chromosome 6 consists of three THE HLA SYSTEM letters: the first (D) indicates the class, the second (M, O, P, Q, or R) the family, and the third (A or B) First of Two Parts the chain (a or b, respectively). HLA-DRB, for ex- ample, stands for class II genes of the R family cod- JAN KLEIN, PH.D., AND AKIE SATO, PH.D. ing for the b chains. The individual genes of the HLA system are differentiated by Arabic numbers, and the notation for the numerous allelic variants of these MAN dies because his body has rejected a genes is a number preceded by an asterisk. For ex- heart transplant; a woman is crippled by rheu- ample, HLA-DRB1*0401 stands for allelic variant A matoid arthritis; a child goes into a coma that 0401 of gene 1, which encodes the b chain of a class is brought on by cerebral malaria; another child dies II molecule belonging to the R family. Each of the of an infection because of an immunodeficiency; an class II a and b chains has four domains: the pep- elderly man has advanced hepatic cirrhosis caused by tide-binding domain (a1 or b1), the immunoglobu- iron overload.
    [Show full text]
  • Commentary in an Immunological Twilight Zone
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 11504–11505, September 1998 Commentary In an immunological twilight zone Jan Klein* Max-Planck-Institut fu¨r Biologie, Abteilung Immungenetik, Correnstrasse 42, Tu¨bingen, D-72076 Germany Early in their evolution, perhaps during their transition from Ig or simply an Ig variant. To me, the most recent contribution Agnatha (jawless fish) to Gnathostomata (jawed animals), by this group (6) indicates that the doubts were justified. vertebrates committed as much as 1% of their protein- The nurse shark in which Greenberg and his coworkers (5–7) encoding genome to a new system of defense against parasites found the receptor is a representative of cartilaginous fish, the (1). Central to this anticipatory (adaptive) immune system (2) oldest extant branch of jawed vertebrates. The secreted form are three types of antigen receptor—immunoglobulin (Ig), T of the NAR molecule is a homodimer with each chain com- cell receptor (Tcr), and major histocompatibility complex prised of six Ig-like domains—one N terminal V-domain and (Mhc) molecules (3)—each consisting of an antigen-binding five C-domains. The genes coding for the V-domain undergo part and a part concerned with other functions. In the Tcr and somatic diversification in the same way as Tcr and Ig receptors, Ig molecules, both parts, the variable (V) and constant (C) and their products presumably bind antigen, although this domains, are drawn from the multifarious Ig superfamily of point still needs to be demonstrated formally. So is the NAR proteins; in the Mhc molecules, only the part that does not bind an Ig or a Tcr? The authors’ original phylogenetic analysis of antigen comes from the Ig superfamily, whereas the antigen- the five C-domain protein sequences (5) failed to affiliate this binding portion has been derived from a different, as yet part of the NAR unambiguously with either Ig or Tcr, but unidentified source (4).
    [Show full text]