The role of interleukin–15 in T–cell migration and activation in rheumatoid arthritis

Abstract

Interleukin 15 (IL-15) is a novel cytokine with interleukin-2-like activity. It is also a potent T-lymphocyte chemoattractant. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the presence of activated T lymphocytes, macrophages and synoviocytes in the synovial membrane. The mechanisms of T-cell activation in RA are currently unclear. We report the presence of high concentrations of IL-15 in rheumatoid arthritis (RA) synovial fluid and have demonstrated its expression in the synovial membrane lining layer by immunohistochemistry. RA synovial fluids were found to contain chemotactic activity, which was attributable in part to the presence of IL-15. Moreover, in a murine model, injection of recombinant IL-15 was found to induce a local tissue inflammatory infiltrate consisting predominantly of T lymphocytes. Synovial fluid T lymphocytes proliferate in response to IL-15, demonstrating that continued responsiveness to IL-15 is a feature of T cells after entry into the synovial compartment. These data suggest that IL-15 can recruit and activate T lymphocytes in the synovial membrane, thereby contributing to RA pathogenesis.

Pathogenic role of the CXCL16–CXCR6 pathway in rheumatoid arthritis

“…Taken together, these results indicate that CXCL16 could induce migration of CXCR6-positive T cells (which are activated, memory, and type 1 cytokine-producing T cells) from peripheral blood into synovial tissue. It is also possible that migrated CD4 and CD8 T cells are stimulated with IL-15, which is expressed in the RA synovium (36,37), and then express CXCR6. Consequently, CXCL16 could retain the CXCR6-positive CD4 and CD8 T cells in the synovial tissue.…”

“…Previous studies demonstrated the expression of IL-15 on synoviocytes and synovial endothelial cells in RA (36,37). Although a few peripheral blood T cells expressed CXCR6 ( Figure 3A), stimulation with 30 ng/ml of IL-15 for 8 days significantly increased CXCR6 expression in vitro (for CD4, mean Ϯ SEM 30.2 Ϯ 6.5%; for CD8, 16.9 Ϯ 1.4% [P Ͻ 0.05]; n ϭ 5) compared with expression without IL-15 stimulation (for CD4, 4.0 Ϯ 1.0%; for CD8, 7.1 Ϯ 2.0%; n ϭ 5); these findings are similar to those previously reported (38).…”

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

“…To understand the underlying immunological mechanisms leading to Treg deficiency in SLE, we focused on the roles of IL-2 and IL-15, two cytokines known to be critically involved in the differentiation and expansion of both Teff and Treg [41][42][43]46]. It has recently been shown that production of functional Treg may occur in the thymus independent of IL-2, but the survival and expansion of peripheral Treg are greatly reduced in the absence of IL-2 [26].…”

“…The imbalanced IL-2 versus IFN-c production therefore also reflects the dysregulated Teff functions. IL-15 is a pleiotropic cytokine akin to IL-2 [41,42], which is produced by monocytic cells including DC [48,49] rather than T cells. IL-15 mediates its functions through the b-and c-chains of the IL-2 receptor together with a unique IL-15 a-chain, and is known to be involved in the regulation of normal differentiation and expansion of T cells including Treg [43].…”

“…IL-15 is a cytokine with many biological activities similar to IL-2 [41,42], known to be involved in the regulation of normal differentiation and expansion of T cells including Treg [43]. Therefore, we also examined the role of IL-15 in our mouse model.…”