T Cell Migration in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in joints, associated with synovial hyperplasia and with bone and cartilage destruction. Although the primacy of T cell-related events early in the disease continues to be debated, there is strong evidence that autoantigen recognition by specific T cells is crucial to the pathophysiology of rheumatoid synovitis. In addition, T cells are key components of the immune cell infiltrate detected in the joints of RA patients. Initial analysis of the cytokines released into the synovial membrane showed an imbalance, with a predominance of proinflammatory mediators, indicating a deleterious effect of Th1 T cells. There is nonetheless evidence that Th17 cells also play an important role in RA. T cells migrate from the bloodstream to the synovial tissue via their interactions with the endothelial cells that line synovial postcapillary venules. At this stage, selectins, integrins, and chemokines have a central role in blood cell invasion of synovial tissue, and therefore in the intensity of the inflammatory response. In this review, we will focus on the mechanisms involved in T cell attraction to the joint, the proteins involved in their extravasation from blood vessels, and the signaling pathways activated. Knowledge of these processes will lead to a better understanding of the mechanism by which the systemic immune response causes local joint disorders and will help to provide a molecular basis for therapeutic strategies.

Keywords: cell migration; chemokines; cytokines; inflammation; rheumatoid arthritis.

Figure 1

Cell types, cytokines, and chemokine receptors involved in rheumatoid arthritis development. Environmental factors and susceptibility gene interactions promote loss of tolerance to citrullinated self proteins generated by post-translational modifications. Co-stimulation-dependent interactions among DCs, T cells, and B cells generate an autoimmune response to these self proteins. This inflammatory process occurs primarily in the lymph node, but also in the inflamed joint. Adaptive and innate immune cells are attracted to the joint where immune pathways integrate to promote tissue remodeling and damage. Positive feedback loops mediated by interactions among leukocytes, synovial fibroblasts, chondrocytes, and osteoclasts, together with the molecular products of damage, drive the chronic phase in rheumatoid arthritis (RA) pathogenesis. High levels of activated memory CD4⁺ and CD8⁺ T cells differentiated through cytokine stimulation of naïve cells infiltrate the synovia (A). RA was classically considered a type 1 T helper (Th1)-mediated disease, but today data indicate that type 17 T helper cells (Th17) are more important in its promotion. Evidence shows that type 22 T helper cells (Th22) also contribute to RA pathogenesis. Function of regulatory T cells (Treg) is also reduced and effector cell resistance to suppression thus helps to alter the immune balance in inflamed joints. The figure shows the chemokine receptor expression pattern (B) and the main secreted cytokines (C) associated with each T cell subtype.

Figure 2

Extravasation model for T cells at the inflamed joint. In response to proinflammatory mediators, leukocytes and vascular cells are activated. Among other immune cells, T cells (Th1, Th17, Treg, and possibly Th22) initiate a serial cascade (rolling, arrest, spreading, crawling, and transmigration) and eventually extravasate from blood vessels to the inflamed joint. The figure shows inflammatory cytokines, selectins, integrins, adhesion molecules, chemokines, and chemokine receptors involved in T cell recruitment to and retention in the joint.