Abstract
Clonal expansion of CD4+ T cells is a characteristic finding in patients with RA and is only infrequently found in patients with psoriatic arthritis and healthy controls. Expanded CD4+ clonotypes are present in the blood, infiltrate into the joint, and persist over years. We have not addressed the question of whether the expanded clonotypes have unique functional and phenotypic properties which may explain the preferential in vivo expansion in RA. In contrast to most CD4+ T cells, expanded clonotypes lacked the expression of the CD28 and CD7 cell surface molecules. Accordingly, the subsets of CD4+ CD28- (9.7 vs 1.7, P = 0.00002) and CD4+ CD7- T cells (21.5 vs 12.26, P = 0.018) were increased in RA patients compared with age-matched normal individuals. Despite the lack of CD28 expression, clonally expanded CD4+ T cells were not anergic but proliferated in response to immobilized anti-CD3 and could be maintained in tissue culture. In vivo expanded CD4+ T cells were autoreactive to ubiquitously distributed autoantigens. They responded in an autologous mixed lymphocyte reaction, and T cell clones isolated from selected patients proliferated to autologous peripheral blood adherent cells. These data suggest that in RA patients selected CD4+ T cells which share the CD7- CD28- phenotype escape from peripheral tolerance.
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- Akbar A. N., Borthwick N., Salmon M., Gombert W., Bofill M., Shamsadeen N., Pilling D., Pett S., Grundy J. E., Janossy G. The significance of low bcl-2 expression by CD45RO T cells in normal individuals and patients with acute viral infections. The role of apoptosis in T cell memory. J Exp Med. 1993 Aug 1;178(2):427–438. doi: 10.1084/jem.178.2.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Autran B., Legac E., Blanc C., Debré P. A Th0/Th2-like function of CD4+CD7- T helper cells from normal donors and HIV-infected patients. J Immunol. 1995 Feb 1;154(3):1408–1417. [PubMed] [Google Scholar]
- Azuma M., Phillips J. H., Lanier L. L. CD28- T lymphocytes. Antigenic and functional properties. J Immunol. 1993 Feb 15;150(4):1147–1159. [PubMed] [Google Scholar]
- Bell E. B., Sparshott S. M. Interconversion of CD45R subsets of CD4 T cells in vivo. Nature. 1990 Nov 8;348(6297):163–166. doi: 10.1038/348163a0. [DOI] [PubMed] [Google Scholar]
- Bendelac A., Killeen N., Littman D. R., Schwartz R. H. A subset of CD4+ thymocytes selected by MHC class I molecules. Science. 1994 Mar 25;263(5154):1774–1778. doi: 10.1126/science.7907820. [DOI] [PubMed] [Google Scholar]
- Boise L. H., Minn A. J., Noel P. J., June C. H., Accavitti M. A., Lindsten T., Thompson C. B. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity. 1995 Jul;3(1):87–98. doi: 10.1016/1074-7613(95)90161-2. [DOI] [PubMed] [Google Scholar]
- Brunner T., Mogil R. J., LaFace D., Yoo N. J., Mahboubi A., Echeverri F., Martin S. J., Force W. R., Lynch D. H., Ware C. F. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature. 1995 Feb 2;373(6513):441–444. doi: 10.1038/373441a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Cohen J. J., Duke R. C., Fadok V. A., Sellins K. S. Apoptosis and programmed cell death in immunity. Annu Rev Immunol. 1992;10:267–293. doi: 10.1146/annurev.iy.10.040192.001411. [DOI] [PubMed] [Google Scholar]
- DerSimonian H., Sugita M., Glass D. N., Maier A. L., Weinblatt M. E., Rème T., Brenner M. B. Clonal V alpha 12.1+ T cell expansions in the peripheral blood of rheumatoid arthritis patients. J Exp Med. 1993 Jun 1;177(6):1623–1631. doi: 10.1084/jem.177.6.1623. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dhein J., Walczak H., Bäumler C., Debatin K. M., Krammer P. H. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) Nature. 1995 Feb 2;373(6513):438–441. doi: 10.1038/373438a0. [DOI] [PubMed] [Google Scholar]
- Fitzgerald J. E., Ricalton N. S., Meyer A. C., West S. G., Kaplan H., Behrendt C., Kotzin B. L. Analysis of clonal CD8+ T cell expansions in normal individuals and patients with rheumatoid arthritis. J Immunol. 1995 Apr 1;154(7):3538–3547. [PubMed] [Google Scholar]
- Goronzy J. J., Bartz-Bazzanella P., Hu W., Jendro M. C., Walser-Kuntz D. R., Weyand C. M. Dominant clonotypes in the repertoire of peripheral CD4+ T cells in rheumatoid arthritis. J Clin Invest. 1994 Nov;94(5):2068–2076. doi: 10.1172/JCI117561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Harris E. D., Jr Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990 May 3;322(18):1277–1289. doi: 10.1056/NEJM199005033221805. [DOI] [PubMed] [Google Scholar]
- Haynes B. F., Metzgar R. S., Minna J. D., Bunn P. A. Phenotypic characterization of cutaneous T-cell lymphoma. Use of monoclonal antibodies to compare with other malignant T cells. N Engl J Med. 1981 May 28;304(22):1319–1323. doi: 10.1056/NEJM198105283042202. [DOI] [PubMed] [Google Scholar]
- Hingorani R., Choi I. H., Akolkar P., Gulwani-Akolkar B., Pergolizzi R., Silver J., Gregersen P. K. Clonal predominance of T cell receptors within the CD8+ CD45RO+ subset in normal human subjects. J Immunol. 1993 Nov 15;151(10):5762–5769. [PubMed] [Google Scholar]
- Jenkins M. K., Johnson J. G. Molecules involved in T-cell costimulation. Curr Opin Immunol. 1993 Jun;5(3):361–367. doi: 10.1016/0952-7915(93)90054-v. [DOI] [PubMed] [Google Scholar]
- Jevnikar A. M., Grusby M. J., Glimcher L. H. Prevention of nephritis in major histocompatibility complex class II-deficient MRL-lpr mice. J Exp Med. 1994 Apr 1;179(4):1137–1143. doi: 10.1084/jem.179.4.1137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ju S. T., Panka D. J., Cui H., Ettinger R., el-Khatib M., Sherr D. H., Stanger B. Z., Marshak-Rothstein A. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature. 1995 Feb 2;373(6513):444–448. doi: 10.1038/373444a0. [DOI] [PubMed] [Google Scholar]
- Lantz O., Bendelac A. An invariant T cell receptor alpha chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans. J Exp Med. 1994 Sep 1;180(3):1097–1106. doi: 10.1084/jem.180.3.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lazarovits A. I., White M. J., Karsh J. CD7- T cells in rheumatoid arthritis. Arthritis Rheum. 1992 Jun;35(6):615–624. doi: 10.1002/art.1780350604. [DOI] [PubMed] [Google Scholar]
- Legac E., Autran B., Merle-Beral H., Katlama C., Debre P. CD4+CD7-CD57+ T cells: a new T-lymphocyte subset expanded during human immunodeficiency virus infection. Blood. 1992 Apr 1;79(7):1746–1753. [PubMed] [Google Scholar]
- Linsley P. S., Ledbetter J. A. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol. 1993;11:191–212. doi: 10.1146/annurev.iy.11.040193.001203. [DOI] [PubMed] [Google Scholar]
- Lynch D. H., Watson M. L., Alderson M. R., Baum P. R., Miller R. E., Tough T., Gibson M., Davis-Smith T., Smith C. A., Hunter K. The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster. Immunity. 1994 May;1(2):131–136. doi: 10.1016/1074-7613(94)90106-6. [DOI] [PubMed] [Google Scholar]
- Moll M., Reinhold U., Kukel S., Abken H., Müller R., Oltermann I., Kreysel H. W. CD7-negative helper T cells accumulate in inflammatory skin lesions. J Invest Dermatol. 1994 Mar;102(3):328–332. doi: 10.1111/1523-1747.ep12371791. [DOI] [PubMed] [Google Scholar]
- Morishita Y., Sao H., Hansen J. A., Martin P. J. A distinct subset of human CD4+ cells with a limited alloreactive T cell receptor repertoire. J Immunol. 1989 Nov 1;143(9):2783–2789. [PubMed] [Google Scholar]
- Morley J. K., Batliwalla F. M., Hingorani R., Gregersen P. K. Oligoclonal CD8+ T cells are preferentially expanded in the CD57+ subset. J Immunol. 1995 Jun 1;154(11):6182–6190. [PubMed] [Google Scholar]
- Moskophidis D., Lechner F., Pircher H., Zinkernagel R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993 Apr 22;362(6422):758–761. doi: 10.1038/362758a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Ramsdell F., Seaman M. S., Miller R. E., Picha K. S., Kennedy M. K., Lynch D. H. Differential ability of Th1 and Th2 T cells to express Fas ligand and to undergo activation-induced cell death. Int Immunol. 1994 Oct;6(10):1545–1553. doi: 10.1093/intimm/6.10.1545. [DOI] [PubMed] [Google Scholar]
- Reinhold U., Abken H., Kukel S., Moll M., Müller R., Oltermann I., Kreysel H. W. CD7- T cells represent a subset of normal human blood lymphocytes. J Immunol. 1993 Mar 1;150(5):2081–2089. [PubMed] [Google Scholar]
- Rothstein D. M., Yamada A., Schlossman S. F., Morimoto C. Cyclic regulation of CD45 isoform expression in a long term human CD4+CD45RA+ T cell line. J Immunol. 1991 Feb 15;146(4):1175–1183. [PubMed] [Google Scholar]
- Singer G. G., Abbas A. K. The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity. 1994 Aug;1(5):365–371. doi: 10.1016/1074-7613(94)90067-1. [DOI] [PubMed] [Google Scholar]
- Stoflet E. S., Koeberl D. D., Sarkar G., Sommer S. S. Genomic amplification with transcript sequencing. Science. 1988 Jan 29;239(4839):491–494. doi: 10.1126/science.3340835. [DOI] [PubMed] [Google Scholar]
- Van Boxel J. A., Paget S. A. Predominantly T-cell infiltrate in rheumatoid synovial membranes. N Engl J Med. 1975 Sep 11;293(11):517–520. doi: 10.1056/NEJM197509112931101. [DOI] [PubMed] [Google Scholar]
- Walser-Kuntz D. R., Weyand C. M., Weaver A. J., O'Fallon W. M., Goronzy J. J. Mechanisms underlying the formation of the T cell receptor repertoire in rheumatoid arthritis. Immunity. 1995 Jun;2(6):597–605. doi: 10.1016/1074-7613(95)90004-7. [DOI] [PubMed] [Google Scholar]
- Watanabe-Fukunaga R., Brannan C. I., Copeland N. G., Jenkins N. A., Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992 Mar 26;356(6367):314–317. doi: 10.1038/356314a0. [DOI] [PubMed] [Google Scholar]
- Webb S., Morris C., Sprent J. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell. 1990 Dec 21;63(6):1249–1256. doi: 10.1016/0092-8674(90)90420-j. [DOI] [PubMed] [Google Scholar]
- Weyand C. M., Xie C., Goronzy J. J. Homozygosity for the HLA-DRB1 allele selects for extraarticular manifestations in rheumatoid arthritis. J Clin Invest. 1992 Jun;89(6):2033–2039. doi: 10.1172/JCI115814. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wordsworth P., Pile K. D., Buckely J. D., Lanchbury J. S., Ollier B., Lathrop M., Bell J. I. HLA heterozygosity contributes to susceptibility to rheumatoid arthritis. Am J Hum Genet. 1992 Sep;51(3):585–591. [PMC free article] [PubMed] [Google Scholar]