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. 1995 Feb 1;181(2):503–513. doi: 10.1084/jem.181.2.503

In vivo expansion of HLA-B35 alloreactive T cells sharing homologous T cell receptors: evidence for maintenance of an oligoclonally dominated allospecificity by persistent stimulation with an autologous MHC/peptide complex

PMCID: PMC2191865  PMID: 7836907

Abstract

The nature of alloantigens seen by T lymphocytes, in particular the role of peptides in allorecognition, has been studied intensively whereas knowledge about the in vivo emergence, diversity, and the structural basis of specificity of alloreactive T cells is very limited. Here we describe human T cell clones that recognize HLA-B35 alloantigens in a peptide-dependent manner. TCR sequence analysis revealed that several of these allospecific clones utilize homologous TCR: they all express TCRAV2S3J36C1 and TCRBV4S1J2S7C2 chains with highly related CDR3 sequences. Thus peptide-specific alloreactivity is reflected in homologous CDR3 sequences in a manner similar to that described for T cells that recognize nominal peptide/self-MHC complexes. The in vivo frequency of this TCR specificity was studied in unstimulated PBL of the responding cell donor who was not sensitized against HLA-B35. The vast majority (approximately 75%) of the VA2S3J36 junctional regions obtained from two samples of PBL, isolated at a 9-yr interval, encode CDR3 identical or homologous to those of the functionally characterized HLA-B35 allospecific T cells. These data are most easily explained by a model of alloreactivity in which persistent or recurrent exposure to a foreign peptide/self-MHC complex led to the in vivo expansion and long-term maintenance of specific T cells that show fortuitous crossrecognition of an HLA-B35/peptide complex and dominate the alloresponse against HLA-B35.

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Selected References

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  1. Alexander J., Payne J. A., Murray R., Frelinger J. A., Cresswell P. Differential transport requirements of HLA and H-2 class I glycoproteins. Immunogenetics. 1989;29(6):380–388. doi: 10.1007/BF00375866. [DOI] [PubMed] [Google Scholar]
  2. Ashwell J. D., Chen C., Schwartz R. H. High frequency and nonrandom distribution of alloreactivity in T cell clones selected for recognition of foreign antigen in association with self class II molecules. J Immunol. 1986 Jan;136(2):389–395. [PubMed] [Google Scholar]
  3. Barber L. D., Parham P. Peptide binding to major histocompatibility complex molecules. Annu Rev Cell Biol. 1993;9:163–206. doi: 10.1146/annurev.cb.09.110193.001115. [DOI] [PubMed] [Google Scholar]
  4. Bevan M. J., Hogquist K. A., Jameson S. C. Selecting the T cell receptor repertoire. Science. 1994 May 6;264(5160):796–797. doi: 10.1126/science.8171333. [DOI] [PubMed] [Google Scholar]
  5. Bill J., Yagüe J., Appel V. B., White J., Horn G., Erlich H. A., Palmer E. Molecular genetic analysis of 178 I-Abm12-reactive T cells. J Exp Med. 1989 Jan 1;169(1):115–133. doi: 10.1084/jem.169.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bowness P., Moss P. A., Rowland-Jones S., Bell J. I., McMichael A. J. Conservation of T cell receptor usage by HLA B27-restricted influenza-specific cytotoxic T lymphocytes suggests a general pattern for antigen-specific major histocompatibility complex class I-restricted responses. Eur J Immunol. 1993 Jul;23(7):1417–1421. doi: 10.1002/eji.1830230702. [DOI] [PubMed] [Google Scholar]
  7. Broeren C. P., Verjans G. M., Van Eden W., Kusters J. G., Lenstra J. A., Logtenberg T. Conserved nucleotide sequences at the 5' end of T cell receptor variable genes facilitate polymerase chain reaction amplification. Eur J Immunol. 1991 Mar;21(3):569–575. doi: 10.1002/eji.1830210306. [DOI] [PubMed] [Google Scholar]
  8. Burrows S. R., Khanna R., Burrows J. M., Moss D. J. An alloresponse in humans is dominated by cytotoxic T lymphocytes (CTL) cross-reactive with a single Epstein-Barr virus CTL epitope: implications for graft-versus-host disease. J Exp Med. 1994 Apr 1;179(4):1155–1161. doi: 10.1084/jem.179.4.1155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Choi Y. W., Kotzin B., Herron L., Callahan J., Marrack P., Kappler J. Interaction of Staphylococcus aureus toxin "superantigens" with human T cells. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8941–8945. doi: 10.1073/pnas.86.22.8941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Crumpacker D. B., Alexander J., Cresswell P., Engelhard V. H. Role of endogenous peptides in murine allogenic cytotoxic T cell responses assessed using transfectants of the antigen-processing mutant 174xCEM.T2. J Immunol. 1992 May 15;148(10):3004–3011. [PubMed] [Google Scholar]
  11. Davies T. F., Martin A., Concepcion E. S., Graves P., Cohen L., Ben-Nun A. Evidence of limited variability of antigen receptors on intrathyroidal T cells in autoimmune thyroid disease. N Engl J Med. 1991 Jul 25;325(4):238–244. doi: 10.1056/NEJM199107253250404. [DOI] [PubMed] [Google Scholar]
  12. Davis M. M., Bjorkman P. J. T-cell antigen receptor genes and T-cell recognition. Nature. 1988 Aug 4;334(6181):395–402. doi: 10.1038/334395a0. [DOI] [PubMed] [Google Scholar]
  13. Engel I., Hedrick S. M. Site-directed mutations in the VDJ junctional region of a T cell receptor beta chain cause changes in antigenic peptide recognition. Cell. 1988 Aug 12;54(4):473–484. doi: 10.1016/0092-8674(88)90068-2. [DOI] [PubMed] [Google Scholar]
  14. Geiger M. J., Gorski J., Eckels D. D. T cell receptor gene segment utilization by HLA-DR1-alloreactive T cell clones. J Immunol. 1991 Oct 1;147(7):2082–2087. [PubMed] [Google Scholar]
  15. Goss J. A., Alexander-Miller M. A., Gorka J., Flye M. W., Connolly J. M., Hansen T. H. Specific prolongation of allograft survival by a T-cell-receptor-derived peptide. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9872–9876. doi: 10.1073/pnas.90.21.9872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gulwani-Akolkar B., Posnett D. N., Janson C. H., Grunewald J., Wigzell H., Akolkar P., Gregersen P. K., Silver J. T cell receptor V-segment frequencies in peripheral blood T cells correlate with human leukocyte antigen type. J Exp Med. 1991 Nov 1;174(5):1139–1146. doi: 10.1084/jem.174.5.1139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Heath W. R., Kane K. P., Mescher M. F., Sherman L. A. Alloreactive T cells discriminate among a diverse set of endogenous peptides. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5101–5105. doi: 10.1073/pnas.88.12.5101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hunt D. F., Henderson R. A., Shabanowitz J., Sakaguchi K., Michel H., Sevilir N., Cox A. L., Appella E., Engelhard V. H. Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science. 1992 Mar 6;255(5049):1261–1263. doi: 10.1126/science.1546328. [DOI] [PubMed] [Google Scholar]
  19. Hünig T., Bevan M. J. Specificity of T-cell cones illustrates altered self hypothesis. Nature. 1981 Dec 3;294(5840):460–462. doi: 10.1038/294460a0. [DOI] [PubMed] [Google Scholar]
  20. Jorgensen J. L., Reay P. A., Ehrich E. W., Davis M. M. Molecular components of T-cell recognition. Annu Rev Immunol. 1992;10:835–873. doi: 10.1146/annurev.iy.10.040192.004155. [DOI] [PubMed] [Google Scholar]
  21. Kelly A., Powis S. H., Kerr L. A., Mockridge I., Elliott T., Bastin J., Uchanska-Ziegler B., Ziegler A., Trowsdale J., Townsend A. Assembly and function of the two ABC transporter proteins encoded in the human major histocompatibility complex. Nature. 1992 Feb 13;355(6361):641–644. doi: 10.1038/355641a0. [DOI] [PubMed] [Google Scholar]
  22. Kelly J. M., Sterry S. J., Cose S., Turner S. J., Fecondo J., Rodda S., Fink P. J., Carbone F. R. Identification of conserved T cell receptor CDR3 residues contacting known exposed peptide side chains from a major histocompatibility complex class I-bound determinant. Eur J Immunol. 1993 Dec;23(12):3318–3326. doi: 10.1002/eji.1830231239. [DOI] [PubMed] [Google Scholar]
  23. Lauzurica P., Bragado R., López D., Galocha B., López de Castro J. A. Asymmetric selection of T cell antigen receptor alpha- and beta-chains in HLA-B27 alloreactivity. J Immunol. 1992 Jun 1;148(11):3624–3630. [PubMed] [Google Scholar]
  24. Lechler R., Lombardi G. Structural aspects of allorecognition. Curr Opin Immunol. 1991 Oct;3(5):715–721. doi: 10.1016/0952-7915(91)90102-7. [DOI] [PubMed] [Google Scholar]
  25. MacDonald H. R., Casanova J. L., Maryanski J. L., Cerottini J. C. Oligoclonal expansion of major histocompatibility complex class I-restricted cytolytic T lymphocytes during a primary immune response in vivo: direct monitoring by flow cytometry and polymerase chain reaction. J Exp Med. 1993 May 1;177(5):1487–1492. doi: 10.1084/jem.177.5.1487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Malissen M., Trucy J., Letourneur F., Rebaï N., Dunn D. E., Fitch F. W., Hood L., Malissen B. A T cell clone expresses two T cell receptor alpha genes but uses one alpha beta heterodimer for allorecognition and self MHC-restricted antigen recognition. Cell. 1988 Oct 7;55(1):49–59. doi: 10.1016/0092-8674(88)90008-6. [DOI] [PubMed] [Google Scholar]
  27. Mason D. W., Morris P. J. Effector mechanisms in allograft rejection. Annu Rev Immunol. 1986;4:119–145. doi: 10.1146/annurev.iy.04.040186.001003. [DOI] [PubMed] [Google Scholar]
  28. Matis L. A., Sorger S. B., McElligott D. L., Fink P. J., Hedrick S. M. The molecular basis of alloreactivity in antigen-specific, major histocompatibility complex-restricted T cell clones. Cell. 1987 Oct 9;51(1):59–69. doi: 10.1016/0092-8674(87)90010-9. [DOI] [PubMed] [Google Scholar]
  29. Miceli M. C., Finn O. J. T cell receptor beta-chain selection in human allograft rejection. J Immunol. 1989 Jan 1;142(1):81–86. [PubMed] [Google Scholar]
  30. Moss P. A., Moots R. J., Rosenberg W. M., Rowland-Jones S. J., Bodmer H. C., McMichael A. J., Bell J. I. Extensive conservation of alpha and beta chains of the human T-cell antigen receptor recognizing HLA-A2 and influenza A matrix peptide. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8987–8990. doi: 10.1073/pnas.88.20.8987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Moss P. A., Rosenberg W. M., Zintzaras E., Bell J. I. Characterization of the human T cell receptor alpha-chain repertoire and demonstration of a genetic influence on V alpha usage. Eur J Immunol. 1993 May;23(5):1153–1159. doi: 10.1002/eji.1830230526. [DOI] [PubMed] [Google Scholar]
  32. Posnett D. N., Sinha R., Kabak S., Russo C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy". J Exp Med. 1994 Feb 1;179(2):609–618. doi: 10.1084/jem.179.2.609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rammensee H. G., Falk K., Rötzschke O. Peptides naturally presented by MHC class I molecules. Annu Rev Immunol. 1993;11:213–244. doi: 10.1146/annurev.iy.11.040193.001241. [DOI] [PubMed] [Google Scholar]
  34. Reinhardt C., Falk C., Steinle A., Schendel D. J. MHC class I allorecognition: the likes and dislikes of CTL and NK cells. Behring Inst Mitt. 1994 Jul;(94):61–71. [PubMed] [Google Scholar]
  35. Rosenberg W. M., Moss P. A., Bell J. I. Variation in human T cell receptor V beta and J beta repertoire: analysis using anchor polymerase chain reaction. Eur J Immunol. 1992 Feb;22(2):541–549. doi: 10.1002/eji.1830220237. [DOI] [PubMed] [Google Scholar]
  36. Rötzschke O., Falk K., Faath S., Rammensee H. G. On the nature of peptides involved in T cell alloreactivity. J Exp Med. 1991 Nov 1;174(5):1059–1071. doi: 10.1084/jem.174.5.1059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Salter R. D., Cresswell P. Impaired assembly and transport of HLA-A and -B antigens in a mutant TxB cell hybrid. EMBO J. 1986 May;5(5):943–949. doi: 10.1002/j.1460-2075.1986.tb04307.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Salter R. D., Howell D. N., Cresswell P. Genes regulating HLA class I antigen expression in T-B lymphoblast hybrids. Immunogenetics. 1985;21(3):235–246. doi: 10.1007/BF00375376. [DOI] [PubMed] [Google Scholar]
  39. Schendel D. J., Wank R., Dupont B. Standardization of the human in vitro cell-mediated lympholysis technique. Tissue Antigens. 1979 Feb;13(2):112–120. doi: 10.1111/j.1399-0039.1979.tb01146.x. [DOI] [PubMed] [Google Scholar]
  40. Sherman L. A., Chattopadhyay S. The molecular basis of allorecognition. Annu Rev Immunol. 1993;11:385–402. doi: 10.1146/annurev.iy.11.040193.002125. [DOI] [PubMed] [Google Scholar]
  41. Shimizu Y., DeMars R. Production of human cells expressing individual transferred HLA-A,-B,-C genes using an HLA-A,-B,-C null human cell line. J Immunol. 1989 May 1;142(9):3320–3328. [PubMed] [Google Scholar]
  42. Spies T., Bresnahan M., Bahram S., Arnold D., Blanck G., Mellins E., Pious D., DeMars R. A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway. Nature. 1990 Dec 20;348(6303):744–747. doi: 10.1038/348744a0. [DOI] [PubMed] [Google Scholar]
  43. Sredni B., Schwartz R. H. Alloreactivity of an antigen-specific T-cell clone. Nature. 1980 Oct 30;287(5785):855–857. doi: 10.1038/287855a0. [DOI] [PubMed] [Google Scholar]
  44. Steinle A., Reinhardt C., Nössner E., Uchanska-Ziegler B., Ziegler A., Schendel D. J. Microheterogeneity in HLA-B35 alleles influences peptide-dependent allorecognition by cytotoxic T cells but not binding of a peptide-restricted monoclonal antibody. Hum Immunol. 1993 Dec;38(4):261–269. doi: 10.1016/0198-8859(93)90553-d. [DOI] [PubMed] [Google Scholar]
  45. Sugden B., Marsh K., Yates J. A vector that replicates as a plasmid and can be efficiently selected in B-lymphoblasts transformed by Epstein-Barr virus. Mol Cell Biol. 1985 Feb;5(2):410–413. doi: 10.1128/mcb.5.2.410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Theiler G., Pando M., Delfino J. M., Takiguchi M., Satz M. L. Isolation and characterization of two new functional subtypes of HLA-B35. Tissue Antigens. 1993 Mar;41(3):143–147. doi: 10.1111/j.1399-0039.1993.tb01993.x. [DOI] [PubMed] [Google Scholar]
  47. Uchańska-Ziegler B., Nössner E., Schenk A., Ziegler A., Schendel D. J. Soluble T cell receptor-like properties of an HLA-B35-specific monoclonal antibody (TU165). Eur J Immunol. 1993 Mar;23(3):734–738. doi: 10.1002/eji.1830230325. [DOI] [PubMed] [Google Scholar]
  48. von Boehmer H. Thymic selection: a matter of life and death. Immunol Today. 1992 Nov;13(11):454–458. doi: 10.1016/0167-5699(92)90075-I. [DOI] [PubMed] [Google Scholar]

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