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Mol Med. 1996 September; 2(5): 608–618.
PMCID: PMC2230198

The repertoire of CD4+ CD28- T cells in rheumatoid arthritis.

Abstract

BACKGROUND: While oligoclonality of circulating CD4- CD8 and of CD8+ T cells is not uncommon, clonal dominance within the CD4 compartment is not frequently found in healthy individuals. In contrast, the majority of patients with rheumatoid arthritis (RA) have clonally expanded CD4+ T cell populations. Previous studies have demonstrated that these clonogenic CD4+ T cells do not express the CD28 molecule. To examine the correlation between CD28 expression and clonal proliferation, we have analyzed the T cell receptor (TCR) diversity of CD4+ CD28- T cells in normal individuals and in RA patients. MATERIAL AND METHODS: The size of the peripheral blood CD4+ CD28- compartment was determined in 30 healthy individuals and 30 RA patients by two-color FACS analysis. In 10 RA patients and five controls with more than 2.5% CD4+ CD28- T cells, TCR BV gene segment usage was analyzed with 19 BV-specific antibodies. Oligoclonality was assessed in sorted CD4+ CD28+ and CD28- T cells using TCR BV-BC-specific polymerase chain reaction and size fractionation. Clonal dominance was confirmed by direct sequencing. RESULTS: The CD4+ CD28- T cell compartment was expanded to more than 2.5% in 70% of the RA patients and 30% of the normal individuals. Compared with the CD4+ CD28+ T cells, the TCR BV gene segment usage among CD4+ CD28- cells was grossly skewed with the dominance of single BV elements. Molecular TCR analysis provided evidence for oligoclonality in 17 of 21 expanded BV elements. In two unrelated RA patients who shared both HLA-DRB1 alleles, the TCR beta-chain sequences of dominant clonotypes were highly conserved. CONCLUSIONS: Oligoclonality is a characteristic feature of CD4+ CD28- T cells which are expanded in some healthy individuals and in the majority of RA patients. The lack of CD28 expression is a common denominator of CD4+, CD8+, and CD4- CD8- T cells prone to develop clonal dominance. The limited TCR diversity of clonal CD4+ CD28- populations in RA patients suggests that these T cells recognize a limited spectrum of antigens. The fact that the majority of individuals with marked expansions and oligoclonality of CD4+ CD28- T cells are RA patients suggests a role for these unusual lymphocytes in the pathogenetic events leading to RA.

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Selected References

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  • Davis MM. T cell receptor gene diversity and selection. Annu Rev Biochem. 1990;59:475–496. [PubMed]
  • Blackman M, Kappler J, Marrack P. The role of the T cell receptor in positive and negative selection of developing T cells. Science. 1990 Jun 15;248(4961):1335–1341. [PubMed]
  • Matis LA. The molecular basis of T-cell specificity. Annu Rev Immunol. 1990;8:65–82. [PubMed]
  • Porcelli S, Yockey CE, Brenner MB, Balk SP. Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4-8- alpha/beta T cells demonstrates preferential use of several V beta genes and an invariant TCR alpha chain. J Exp Med. 1993 Jul 1;178(1):1–16. [PMC free article] [PubMed]
  • Callahan JE, Kappler JW, Marrack P. Unexpected expansions of CD8-bearing cells in old mice. J Immunol. 1993 Dec 15;151(12):6657–6669. [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]
  • Monteiro J, Hingorani R, Choi IH, Silver J, Pergolizzi R, Gregersen PK. Oligoclonality in the human CD8+ T cell repertoire in normal subjects and monozygotic twins: implications for studies of infectious and autoimmune diseases. Mol Med. 1995 Sep;1(6):614–624. [PMC free article] [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]
  • Brooks EG, Balk SP, Aupeix K, Colonna M, Strominger JL, Groh-Spies V. Human T-cell receptor (TCR) alpha/beta + CD4-CD8- T cells express oligoclonal TCRs, share junctional motifs across TCR V beta-gene families, and phenotypically resemble memory T cells. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11787–11791. [PubMed]
  • Bendelac A. Mouse NK1+ T cells. Curr Opin Immunol. 1995 Jun;7(3):367–374. [PubMed]
  • Makino Y, Yamagata N, Sasho T, Adachi Y, Kanno R, Koseki H, Kanno M, Taniguchi M. Extrathymic development of V alpha 14-positive T cells. J Exp Med. 1993 May 1;177(5):1399–1408. [PMC free article] [PubMed]
  • Waase I, Kayser C, Carlson PJ, Goronzy JJ, Weyand CM. Oligoclonal T cell proliferation in patients with rheumatoid arthritis and their unaffected siblings. Arthritis Rheum. 1996 Jun;39(6):904–913. [PubMed]
  • Schmidt D, Goronzy JJ, Weyand CM. CD4+ CD7- CD28- T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest. 1996 May 1;97(9):2027–2037. [PMC free article] [PubMed]
  • Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. [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. [PubMed]
  • Pannetier C, Cochet M, Darche S, Casrouge A, Zöller M, Kourilsky P. The sizes of the CDR3 hypervariable regions of the murine T-cell receptor beta chains vary as a function of the recombined germ-line segments. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4319–4323. [PubMed]
  • Gorski J, Yassai M, Zhu X, Kissela B, Kissella B [corrected to Kissela B], Keever C, Flomenberg N. Circulating T cell repertoire complexity in normal individuals and bone marrow recipients analyzed by CDR3 size spectratyping. Correlation with immune status. J Immunol. 1994 May 15;152(10):5109–5119. [PubMed]
  • Stoflet ES, Koeberl DD, Sarkar G, Sommer SS. Genomic amplification with transcript sequencing. Science. 1988 Jan 29;239(4839):491–494. [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]
  • 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]
  • Azuma M, Phillips JH, Lanier LL. CD28- T lymphocytes. Antigenic and functional properties. J Immunol. 1993 Feb 15;150(4):1147–1159. [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]
  • 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]
  • Dellabona P, Padovan E, Casorati G, Brockhaus M, Lanzavecchia A. An invariant V alpha 24-J alpha Q/V beta 11 T cell receptor is expressed in all individuals by clonally expanded CD4-8- T cells. J Exp Med. 1994 Sep 1;180(3):1171–1176. [PMC free article] [PubMed]
  • Casanova JL, Cerottini JC, Matthes M, Necker A, Gournier H, Barra C, Widmann C, MacDonald HR, Lemonnier F, Malissen B, et al. H-2-restricted cytolytic T lymphocytes specific for HLA display T cell receptors of limited diversity. J Exp Med. 1992 Aug 1;176(2):439–447. [PMC free article] [PubMed]
  • Moss PA, Moots RJ, Rosenberg WM, Rowland-Jones SJ, Bodmer HC, McMichael AJ, Bell JI. 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. [PubMed]
  • Jorgensen JL, Reay PA, Ehrich EW, Davis MM. Molecular components of T-cell recognition. Annu Rev Immunol. 1992;10:835–873. [PubMed]
  • Porcelli S, Morita CT, Brenner MB. CD1b restricts the response of human CD4-8- T lymphocytes to a microbial antigen. Nature. 1992 Dec 10;360(6404):593–597. [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]
  • Walunas TL, Sperling AI, Khattri R, Thompson CB, Bluestone JA. CD28 expression is not essential for positive and negative selection of thymocytes or peripheral T cell tolerance. J Immunol. 1996 Feb 1;156(3):1006–1013. [PubMed]
  • Gribben JG, Freeman GJ, Boussiotis VA, Rennert P, Jellis CL, Greenfield E, Barber M, Restivo VA, Jr, Ke X, Gray GS, et al. CTLA4 mediates antigen-specific apoptosis of human T cells. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):811–815. [PubMed]
  • Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995 Nov;3(5):541–547. [PubMed]
  • Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995 Nov 10;270(5238):985–988. [PubMed]
  • Behar SM, Porcelli SA, Beckman EM, Brenner MB. A pathway of costimulation that prevents anergy in CD28- T cells: B7-independent costimulation of CD1-restricted T cells. J Exp Med. 1995 Dec 1;182(6):2007–2018. [PMC free article] [PubMed]

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