Dynamic interactions between T cells and dendritic cells and their derived cytokines/chemokines in the rheumatoid synovium

Abstract

This review focuses on the contributions made by interactions between dendritic cells (DCs) and T cells, and by local production of cytokines and chemokines to the pathogenesis of rheumatoid arthritis (RA) synovitis. DCs are efficient professional antigen-presenting cells, which are critical for the development of innate and adaptative immune responses through interactions with T cells. Cytokines from DCs play a key role in the switch inside effector T-cell pathways. Chemokines are important mediators of the immune response because they regulate leucocyte recruitment to tissue, and they play a key role in inflammatory diseases by acting on T-cell and DC migration. Furthermore, the recently discovered T-helper-17 proinflammatory cytokines, present in syno-vium samples, are associated with the migration, differentiation and maturation of inflammatory cells, and they facilitate a network of interactions between all components of the immune response. An understanding of such interactions is essential because it is the key to therapeutic application.

Figure 1

Role of cytokines in DC and T-cell interactions. Dendritic cells (DCs) produce IL-12 and IL-18; these favour the T-helper (Th)1 pathway, which is characterized by the transcription factor T-bet and the production of IFN-γ. The Th17 pathway results from the combined action of transforming growth factor (TGF)-β plus IL-6 and of IL-23. This pathway is characterized by the transcription factor retinoid-related orphan receptor (ROR)γt and by the production of IL-17. The effector Th1 and Th17 pathways are under the control of the regulatory pathway that is characterized by the transcription factor FoxP3 and the production of TGF-β and IL-10. Defects in this pathway may contribute to the consequences of the chronic RA synovitis that leads to destruction and lack of repair. It should be noted that some of these concepts have been established in the mouse; it is unclear to what extent they apply to humans.

Figure 2

Role of chemokines in the migration of DCs and T-cell subsets in RA synovitis. In response to local inflammation and production of proinflammatory cytokines, after an unknown event CC chemokine receptor (CCR)6⁺ immature dendritic cells (DCs) and T-helper (Th)17 cells are attracted to the synovium in response to local production of CC chemokine ligand (CCL)20 in the perivascular infiltrates and the lining layer. It is also possible that CCR6⁺ cells migrate to the synovial fluid toward CCL20 expressed within the lining layer. The presence of mature DCs in synovium results from the combined effects of cell interactions and cytokine microenvironment. Defects in production of differentiation factors such as IL-4 may favor a relative accumulation of immature DCs. However, detection of CCL19 and CCL21 in perivascular infiltrates and vascular endothelium argues for a direct migration of some CCR7⁺ mature DCs from blood into the synovium, where they can interact with lymphocytes, leading to potent local activation. RA, rheumatoid arthritis.