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Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. May 1, 1996; 97(9): 2027–2037.
PMCID: PMC507276

CD4+ CD7- CD28- T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity.

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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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Van Boxel JA, Paget SA. Predominantly T-cell infiltrate in rheumatoid synovial membranes. N Engl J Med. 1975 Sep 11;293(11):517–520. [PubMed]
  • Harris ED., Jr Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990 May 3;322(18):1277–1289. [PubMed]
  • Wordsworth P, Pile KD, Buckely JD, Lanchbury JS, Ollier B, Lathrop M, Bell JI. HLA heterozygosity contributes to susceptibility to rheumatoid arthritis. Am J Hum Genet. 1992 Sep;51(3):585–591. [PMC free article] [PubMed]
  • Weyand CM, Xie C, Goronzy JJ. Homozygosity for the HLA-DRB1 allele selects for extraarticular manifestations in rheumatoid arthritis. J Clin Invest. 1992 Jun;89(6):2033–2039. [PMC free article] [PubMed]
  • Walser-Kuntz DR, Weyand CM, Weaver AJ, O'Fallon WM, Goronzy JJ. Mechanisms underlying the formation of the T cell receptor repertoire in rheumatoid arthritis. Immunity. 1995 Jun;2(6):597–605. [PubMed]
  • Goronzy JJ, Bartz-Bazzanella P, Hu W, Jendro MC, Walser-Kuntz DR, Weyand CM. Dominant clonotypes in the repertoire of peripheral CD4+ T cells in rheumatoid arthritis. J Clin Invest. 1994 Nov;94(5):2068–2076. [PMC free article] [PubMed]
  • Choi YW, 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. [PMC free article] [PubMed]
  • Stoflet ES, Koeberl DD, Sarkar G, Sommer SS. Genomic amplification with transcript sequencing. Science. 1988 Jan 29;239(4839):491–494. [PubMed]
  • Morishita Y, Sao H, Hansen JA, Martin PJ. 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]
  • Reinhold U, Abken H, Kukel S, Moll M, Müller R, Oltermann I, Kreysel HW. CD7- T cells represent a subset of normal human blood lymphocytes. J Immunol. 1993 Mar 1;150(5):2081–2089. [PubMed]
  • Jenkins MK, Johnson JG. Molecules involved in T-cell costimulation. Curr Opin Immunol. 1993 Jun;5(3):361–367. [PubMed]
  • Linsley PS, Ledbetter JA. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol. 1993;11:191–212. [PubMed]
  • Rothstein DM, Yamada A, Schlossman SF, 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]
  • Bell EB, Sparshott SM. Interconversion of CD45R subsets of CD4 T cells in vivo. Nature. 1990 Nov 8;348(6297):163–166. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Bendelac A, Killeen N, Littman DR, Schwartz RH. A subset of CD4+ thymocytes selected by MHC class I molecules. Science. 1994 Mar 25;263(5154):1774–1778. [PubMed]
  • Lazarovits AI, White MJ, Karsh J. CD7- T cells in rheumatoid arthritis. Arthritis Rheum. 1992 Jun;35(6):615–624. [PubMed]
  • 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]
  • 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]
  • Haynes BF, Metzgar RS, Minna JD, Bunn PA. 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. [PubMed]
  • Moll M, Reinhold U, Kukel S, Abken H, Müller R, Oltermann I, Kreysel HW. CD7-negative helper T cells accumulate in inflammatory skin lesions. J Invest Dermatol. 1994 Mar;102(3):328–332. [PubMed]
  • Azuma M, Phillips JH, Lanier LL. CD28- T lymphocytes. Antigenic and functional properties. J Immunol. 1993 Feb 15;150(4):1147–1159. [PubMed]
  • Posnett DN, 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. [PMC free article] [PubMed]
  • Hingorani R, Choi IH, Akolkar P, Gulwani-Akolkar B, Pergolizzi R, Silver J, Gregersen PK. 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]
  • Morley JK, Batliwalla FM, Hingorani R, Gregersen PK. Oligoclonal CD8+ T cells are preferentially expanded in the CD57+ subset. J Immunol. 1995 Jun 1;154(11):6182–6190. [PubMed]
  • DerSimonian H, Sugita M, Glass DN, Maier AL, Weinblatt ME, Rème T, Brenner MB. 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. [PMC free article] [PubMed]
  • Fitzgerald JE, Ricalton NS, Meyer AC, West SG, Kaplan H, Behrendt C, Kotzin BL. 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]
  • Cohen JJ, Duke RC, Fadok VA, Sellins KS. Apoptosis and programmed cell death in immunity. Annu Rev Immunol. 1992;10:267–293. [PubMed]
  • Dhein J, Walczak H, Bäumler C, Debatin KM, Krammer PH. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) Nature. 1995 Feb 2;373(6513):438–441. [PubMed]
  • Brunner T, Mogil RJ, LaFace D, Yoo NJ, Mahboubi A, Echeverri F, Martin SJ, Force WR, Lynch DH, Ware CF, et al. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature. 1995 Feb 2;373(6513):441–444. [PubMed]
  • Ju ST, Panka DJ, Cui H, Ettinger R, el-Khatib M, Sherr DH, Stanger BZ, Marshak-Rothstein A. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature. 1995 Feb 2;373(6513):444–448. [PubMed]
  • 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. [PubMed]
  • Moskophidis D, Lechner F, Pircher H, Zinkernagel RM. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993 Apr 22;362(6422):758–761. [PubMed]
  • Boise LH, Minn AJ, Noel PJ, June CH, Accavitti MA, Lindsten T, Thompson CB. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity. 1995 Jul;3(1):87–98. [PubMed]
  • Akbar AN, Borthwick N, Salmon M, Gombert W, Bofill M, Shamsadeen N, Pilling D, Pett S, Grundy JE, 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. [PMC free article] [PubMed]
  • Ramsdell F, Seaman MS, Miller RE, Picha KS, Kennedy MK, Lynch DH. 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. [PubMed]
  • Singer GG, Abbas AK. 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. [PubMed]
  • Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992 Mar 26;356(6367):314–317. [PubMed]
  • Lynch DH, Watson ML, Alderson MR, Baum PR, Miller RE, Tough T, Gibson M, Davis-Smith T, Smith CA, Hunter K, et al. 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. [PubMed]
  • Jevnikar AM, Grusby MJ, Glimcher LH. Prevention of nephritis in major histocompatibility complex class II-deficient MRL-lpr mice. J Exp Med. 1994 Apr 1;179(4):1137–1143. [PMC free article] [PubMed]

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