Cells of the synovium in rheumatoid arthritis. T lymphocytes

Abstract

Recent findings have substantiated the importance of T lymphocytes to the pathogenesis of rheumatoid arthritis (RA). Here, we review emerging data regarding genetic predisposition, spontaneous animal models of arthritis, and cell-cell interactions that implicate T cells as driving synovial inflammation and joint destruction. Information regarding the proinflammatory role of interleukin-17-producing T cells and the functional state of regulatory T cells both in animal models and in patients with RA is also discussed. In light of the overwhelming evidence that disrupted T-cell homeostasis greatly contributes to joint pathology in RA, the therapeutic potential of targeting activators of pro-inflammatory T cells or their products is compelling.

Figure 1

Schematic diagram of the putative interactions of pathogenic Th17 cells in the synovial microenvironment. Induction of T-cell responses in rheumatoid arthritis (RA) is initiated by T-cell receptor (TCR) interaction with shared epitope major histocompatibility complex class II (MHCII-SE) and peptide on antigen-presenting cells (APCs) either systemically or in the synovium. Accessory molecules expressed by APCs, including ICAM-1 (intercellular adhesion molecule-1) (CD54), OX40L (CD252), inducible costimulator (ICOS) ligand (CD275), B7-1 (CD80), and B7-2 (CD86), participate in T-cell activation by binding lymphocyte function-associated antigen (LFA)-1 (CD11a/CD18), OX40 (CD134), ICOS (CD278), and CD28. Activated fibroblast-like synoviocytes (FLS) may also participate in antigen presentation and have additional accessory molecules such as LFA-3 (CD58) and ALCAM (activated leukocyte cell adhesion molecule) (CD166) which interact with T cell-expressed CD2 and CD6, respectively. Cytokines interleukin (IL)-6 and transforming growth factor-beta (TGF-β), most likely derived from activated APCs, signal the T cell to differentiate into IL-17-producing Th17 cells. IL-17 has independent and synergistic effects with other proinflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and IL-1β) in the synovium to induce further cytokine release, matrix metalloproteinase production, RANK/RANK ligand (CD265/CD254) expression, and osteoclastogenesis. CD40L (CD154) interaction with CD40 also leads to activation of synovial monocytes/macrophages (Mo/Mac), FLS, and B cells. Although present in the synovia of most patients with RA, CD4⁺CD25^hi regulatory T (Treg) cells are ineffective at controlling inflammation and may be deactivated by synovial TNF-α. IL-10 is abundant in synovial fluid but its effect on Th17 regulation has yet to be determined. Expression of accessory molecules on Th17 cells, as denoted in the figure, are speculative and are inferred from expressions found on non-subdivided T-cell populations in animal models. Further investigation is necessary to directly demonstrate expression of these structures on the Th17 cell subset in human RA synovium. DC, dendritic cell; RANK, receptor activator of nuclear factor-kappa B.