T cell costimulation by fractalkine‐expressing synoviocytes in rheumatoid arthritis

Fractalkine mediates T cell–dependent proliferation of synovial fibroblasts in rheumatoid arthritis

“…Our group previously reported that the T cell pool from patients with RA is enriched for presenescent and senescent CD4 T cells that have lost expression of CD28 and gained alternative immunoregulatory receptors (26,27). CD4ϩ,CD28Ϫ T cells home to both lymph nodes and CCL5-producing synovial lesions (28) and utilize multiple nonconventional receptors to costimulate T cell receptor-mediated signals (11,18). To address the question of whether CD4ϩ,CD28ϩ and CD4ϩ,CD28Ϫ T cells differ in terms of their interaction with FLS and differentially affect FLS proliferation, both T cell subpopulations were isolated from the blood of patients with RA and tested for their growthpromoting capabilities.…”

“…One of the characteristic features of CD4ϩ,CD28Ϫ T cells is the spontaneous expression of CX 3 CR1, the receptor for FKN (18). When partnering with FKN-expressing FLS, CD4ϩ,CD28Ϫ T cells utilize this chemokine receptor to costimulate cytokine production, granule expulsion, and survival.…”

“…Recent work by our group suggests that in RA, the role of FKN extends beyond chemoattraction and adhesion (18). FKN is abundantly expressed on cultured synovial fibroblasts and on hyperplastic synoviocytes in rheumatoid tissue.…”

“…Synovial CD4 T cells use CX 3 CR1 to costimulate T cell receptor-derived signals and respond to cell-bound FKN with the enhanced release of cytokines. CX 3 CR1 is also expressed on synovial cells other than T cells, such as macrophages, dendritic cells, and synovial fibroblasts (18). The synovial microenvironment is rich in FKN (19), an unusual chemokine that exists in both a membrane-integrated and a soluble form.…”

“…When cleaved from the cell membrane, FKN yields a soluble form (sFKN) (19,20). In RA synovium, the major source of FKN is FLS (18), but synovial macrophages and endothelial cells may also produce this chemokine. It is currently believed that FKN mediates all of its biologic actions by binding CX 3 CR1.…”