Inhibition of T cell apoptosis in the rheumatoid synovium.
Abstract
Synovial T cells in rheumatoid arthritis are highly differentiated and express a phenotype suggesting susceptibility to apoptosis (CD45RB dull, CD45RO bright, Bcl-2 low, Bax high, Fas high). However, no evidence of T cell apoptosis was found in synovial fluid from any of 28 patients studied. In contrast, synovial fluid from 10 patients with crystal arthritis showed substantial levels of T cell apoptosis. The failre of apoptosis was not an intrinsic property of rheumatoid synovial T cells, as they showed rapid spontaneous apoptosis on removal from the joint. Synovial T cells from rheumatoid arthritis and gout patients could be rescued from spontaneous apoptosis in vitro either by IL-2R gamma chain signaling cytokines (which upregulate Bcl-2 and Bcl-XL) or by interaction with synovial fibroblasts (which upregulates Bcl-xL but not Bcl-2). The phenotype of rheumatoid synovial T cells ex vivo (Bcl-2 low, Bcl-xL high) suggested a fibroblast-mediated mechanism in vivo. This was confirmed by in vitro culture of synovial T cells with fibroblasts which maintained the Bcl-xL high Bcl-2 low phenotype. Synovial T cells from gout patients were Bcl-2 low Bcl-xL low and showed clear evidence of apoptosis in vivo. Inhibition experiments suggested that an integrin-ligand interaction incorporating the Arg-Gly-Asp motif is involved in fibroblast-mediated synovial T cell survival. We propose that environmental blockade of cell death resulting from interaction with stromal cells is a major factor in the persistent T cell infiltration of chronically inflamed rheumatoid synovium.
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- Salmon M, Gaston JS. The role of T-lymphocytes in rheumatoid arthritis. Br Med Bull. 1995 Apr;51(2):332–345. [PubMed] [Google Scholar]
- Akbar AN, Terry L, Timms A, Beverley PC, Janossy G. Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells. J Immunol. 1988 Apr 1;140(7):2171–2178. [PubMed] [Google Scholar]
- Sanders ME, Makgoba MW, Sharrow SO, Stephany D, Springer TA, Young HA, Shaw S. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-gamma production. J Immunol. 1988 Mar 1;140(5):1401–1407. [PubMed] [Google Scholar]
- Salmon M, Kitas GD, Bacon PA. Production of lymphokine mRNA by CD45R+ and CD45R- helper T cells from human peripheral blood and by human CD4+ T cell clones. J Immunol. 1989 Aug 1;143(3):907–912. [PubMed] [Google Scholar]
- Salmon M, Pilling D, Borthwick NJ, Viner N, Janossy G, Bacon PA, Akbar AN. The progressive differentiation of primed T cells is associated with an increasing susceptibility to apoptosis. Eur J Immunol. 1994 Apr;24(4):892–899. [PubMed] [Google Scholar]
- Mason D, Powrie F. Memory CD4+ T cells in man form two distinct subpopulations, defined by their expression of isoforms of the leucocyte common antigen, CD45. Immunology. 1990 Aug;70(4):427–433.[PMC free article] [PubMed] [Google Scholar]
- Matthews N, Emery P, Pilling D, Akbar A, Salmon M. Subpopulations of primed T helper cells in rheumatoid arthritis. Arthritis Rheum. 1993 May;36(5):603–607. [PubMed] [Google Scholar]
- Thomas R, McIlraith M, Davis LS, Lipsky PE. Rheumatoid synovium is enriched in CD45RBdim mature memory T cells that are potent helpers for B cell differentiation. Arthritis Rheum. 1992 Dec;35(12):1455–1465. [PubMed] [Google Scholar]
- Cohen JJ, Duke RC, Fadok VA, Sellins KS. Apoptosis and programmed cell death in immunity. Annu Rev Immunol. 1992;10:267–293. [PubMed] [Google Scholar]
- 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] [Google Scholar]
- 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] [Google Scholar]
- 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] [Google Scholar]
- Akbar AN, Borthwick NJ, Wickremasinghe RG, Panayoitidis P, Pilling D, Bofill M, Krajewski S, Reed JC, Salmon M. Interleukin-2 receptor common gamma-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax, bcl-xS) gene expression. Eur J Immunol. 1996 Feb;26(2):294–299. [PubMed] [Google Scholar]
- Grabstein KH, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn MA, Ahdieh M, et al. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994 May 13;264(5161):965–968. [PubMed] [Google Scholar]
- Boise LH, González-García M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nuñez G, Thompson CB. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993 Aug 27;74(4):597–608. [PubMed] [Google Scholar]
- Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. [PubMed] [Google Scholar]
- McInnes IB, al-Mughales J, Field M, Leung BP, Huang FP, Dixon R, Sturrock RD, Wilkinson PC, Liew FY. The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nat Med. 1996 Feb;2(2):175–182. [PubMed] [Google Scholar]
- Scott S, Pandolfi F, Kurnick JT. Fibroblasts mediate T cell survival: a proposed mechanism for retention of primed T cells. J Exp Med. 1990 Dec 1;172(6):1873–1876.[PMC free article] [PubMed] [Google Scholar]
- Gombert W, Borthwick NJ, Wallace DL, Hyde H, Bofill M, Pilling D, Beverley PC, Janossy G, Salmon M, Akbar AN. Fibroblasts prevent apoptosis of IL-2-deprived T cells without inducing proliferation: a selective effect on Bcl-XL expression. Immunology. 1996 Nov;89(3):397–404.[PMC free article] [PubMed] [Google Scholar]
- 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] [Google Scholar]
- Pilling D, Kitas GD, Salmon M, Bacon PA. The kinetics of interaction between lymphocytes and magnetic polymer particles. J Immunol Methods. 1989 Sep 1;122(2):235–241. [PubMed] [Google Scholar]
- Grand RJ, Milner AE, Mustoe T, Johnson GD, Owen D, Grant ML, Gregory CD. A novel protein expressed in mammalian cells undergoing apoptosis. Exp Cell Res. 1995 Jun;218(2):439–451. [PubMed] [Google Scholar]
- Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJ. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature. 1989 Jan 12;337(6203):181–184. [PubMed] [Google Scholar]
- Darzynkiewicz Z, Li X, Gong J. Assays of cell viability: discrimination of cells dying by apoptosis. Methods Cell Biol. 1994;41:15–38. [PubMed] [Google Scholar]
- Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods. 1995 Jul 17;184(1):39–51. [PubMed] [Google Scholar]
- Ayroldi E, Cannarile L, Migliorati G, Bartoli A, Nicoletti I, Riccardi C. CD44 (Pgp-1) inhibits CD3 and dexamethasone-induced apoptosis. Blood. 1995 Oct 1;86(7):2672–2678. [PubMed] [Google Scholar]
- Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD. Programmed cell death and the control of cell survival: lessons from the nervous system. Science. 1993 Oct 29;262(5134):695–700. [PubMed] [Google Scholar]
- Giri JG, Ahdieh M, Eisenman J, Shanebeck K, Grabstein K, Kumaki S, Namen A, Park LS, Cosman D, Anderson D. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994 Jun 15;13(12):2822–2830.[PMC free article] [PubMed] [Google Scholar]
- Firestein GS, Yeo M, Zvaifler NJ. Apoptosis in rheumatoid arthritis synovium. J Clin Invest. 1995 Sep;96(3):1631–1638.[PMC free article] [PubMed] [Google Scholar]
- Savill J, Fadok V, Henson P, Haslett C. Phagocyte recognition of cells undergoing apoptosis. Immunol Today. 1993 Mar;14(3):131–136. [PubMed] [Google Scholar]
- Akbar AN, Savill J, Gombert W, Bofill M, Borthwick NJ, Whitelaw F, Grundy J, Janossy G, Salmon M. The specific recognition by macrophages of CD8+,CD45RO+ T cells undergoing apoptosis: a mechanism for T cell clearance during resolution of viral infections. J Exp Med. 1994 Nov 1;180(5):1943–1947.[PMC free article] [PubMed] [Google Scholar]
- Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, Green DR. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med. 1995 Nov 1;182(5):1545–1556.[PMC free article] [PubMed] [Google Scholar]
- Jones ST, Denton J, Holt PJ, Freemont AJ. Possible clearance of effete polymorphonuclear leucocytes from synovial fluid by cytophagocytic mononuclear cells: implications for pathogenesis and chronicity in inflammatory arthritis. Ann Rheum Dis. 1993 Feb;52(2):121–126.[PMC free article] [PubMed] [Google Scholar]
- Hale AJ, Smith CA, Sutherland LC, Stoneman VE, Longthorne VL, Culhane AC, Williams GT. Apoptosis: molecular regulation of cell death. Eur J Biochem. 1996 Feb 15;236(1):1–26. [PubMed] [Google Scholar]
- Stewart M, Thiel M, Hogg N. Leukocyte integrins. Curr Opin Cell Biol. 1995 Oct;7(5):690–696. [PubMed] [Google Scholar]
- Iannone F, Corrigall VM, Kingsley GH, Panayi GS. Evidence for the continuous recruitment and activation of T cells into the joints of patients with rheumatoid arthritis. Eur J Immunol. 1994 Nov;24(11):2706–2713. [PubMed] [Google Scholar]
Abstract
Synovial T cells in rheumatoid arthritis are highly differentiated and express a phenotype suggesting susceptibility to apoptosis (CD45RB dull, CD45RO bright, Bcl-2 low, Bax high, Fas high). However, no evidence of T cell apoptosis was found in synovial fluid from any of 28 patients studied. In contrast, synovial fluid from 10 patients with crystal arthritis showed substantial levels of T cell apoptosis. The failre of apoptosis was not an intrinsic property of rheumatoid synovial T cells, as they showed rapid spontaneous apoptosis on removal from the joint. Synovial T cells from rheumatoid arthritis and gout patients could be rescued from spontaneous apoptosis in vitro either by IL-2R gamma chain signaling cytokines (which upregulate Bcl-2 and Bcl-XL) or by interaction with synovial fibroblasts (which upregulates Bcl-xL but not Bcl-2). The phenotype of rheumatoid synovial T cells ex vivo (Bcl-2 low, Bcl-xL high) suggested a fibroblast-mediated mechanism in vivo. This was confirmed by in vitro culture of synovial T cells with fibroblasts which maintained the Bcl-xL high Bcl-2 low phenotype. Synovial T cells from gout patients were Bcl-2 low Bcl-xL low and showed clear evidence of apoptosis in vivo. Inhibition experiments suggested that an integrin-ligand interaction incorporating the Arg-Gly-Asp motif is involved in fibroblast-mediated synovial T cell survival. We propose that environmental blockade of cell death resulting from interaction with stromal cells is a major factor in the persistent T cell infiltration of chronically inflamed rheumatoid synovium.