Anatomic localization of dendritic cells subsets and plasmacytoid-like Th1 T lymphocytes in rheumatoid synovium: correlation with selective chemokine expression

Rheumatoid arthritis (RA) can be considered as an ectopic lymphoid organ. This suggests a role for chemokines in the migration of T lymphocytes and dendritic cells (DCs) leading to the local organization that is characteristic of the follicular structure of RA synovium. To clarify whether DCs reach the synovium as mature cells or undergo local maturation, we characterized, by immunohistochemistry, the different DC subsets and their association with IL-17 and IFN-γ-producing T cells. The study was done in 12 RA synovium using tonsils as positive control. Immature and mature DCs were defined by expression of CD1a and DC-LAMP/CD83 respectively. Immature CD1a⁺ DCs were mainly detected in the lining layer whereas mature DCs were exclusively detected in the perivascular or lymphocytic infiltrates. The lack of coexpression of DC-LAMP and CD1a indicated the presence of independent immature and mature DC subsets. IL-17 and IFN-γ-producing T cells were detected at the periphery of the lymphocytic infiltrates. They had a plasmacytoid-like appearance but staining for immunoglobulin light chains was negative. A similar morphotype was also observed in stimulted PBMC. To define the DC and Th1 lymphocytes migration pattern, we focused on the expression of chemokines and their associated receptors CCL20/CCR6 controlling the migration of immature DCs and activated T lymphocytes, and CCL21/CCR7, CCL19/CCR7 involved in mature DC and T lymphocyte homing. CCL20 was expressed in the lining layer and to a lower extent in the lymphocytic aggregates. CCL20 colocalized with its receptor CCR6. CCL20-producing cells were associated with CD1a+ immature DCs or IL-17-producing T cells, suggesting the contribution of CCL20 to the homing of CCR6+DC and CCR6+Th1 cells to RA synovium. CCL21 and CCL19 were only detected in the perivascular aggregates as observed for their receptor CCR7. Close association between CCL19, 21, CCR7, and mature DCs or IL-17-producing T cells argues for a role for these chemokines in the homing of CCR7+ DCs and CCR7+IL-17-producing T cells in perivascular infiltrates. The role of DCs and T lymphocytes in disease initiation and perpetuation makes the chemokines, controlling their migration, a potential therapeutic target.