Inhibition of T cell apoptosis in the rheumatoid synovium

J Clin Invest. 1997 Feb 1;99(3):439-46. doi: 10.1172/JCI119178.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / immunology*
  • Arthritis, Gouty / immunology*
  • Arthritis, Rheumatoid / immunology*
  • Cell Survival / physiology
  • Cells, Cultured
  • Coculture Techniques
  • Fibroblasts
  • Flow Cytometry
  • Genes, bcl-2
  • Humans
  • Integrins / physiology
  • Leukocyte Common Antigens / immunology
  • Lymphocyte Activation
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2*
  • Receptors, Interleukin-2 / physiology
  • Signal Transduction
  • Synovial Fluid / immunology*
  • T-Lymphocytes / immunology*
  • Up-Regulation
  • bcl-X Protein

Substances

  • BCL2L1 protein, human
  • Integrins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Interleukin-2
  • bcl-X Protein
  • Leukocyte Common Antigens