Langerhans cells are required for UVR-induced immunosuppression.

Painting of haptens onto UVR-exposed skin does not result in sensitization but induces regulatory T cells (Treg). This was explained by UVR-mediated depletion of Langerhans cells (LCs). Furthermore, migration of UVR-damaged but still viable LCs into lymph nodes appears to be essential to induce Treg. Accordingly, the steroid mometasone, which kills LCs, inhibited sensitization but did not induce Treg. In Langerin-diphtheria toxin receptor knock-in (DTR) mice, LCs can be depleted by injection of diphtheria toxin (DT). LC-depleted mice could be sensitized though less pronounced than wild-type mice, but sensitization was not suppressed by UVR. Similarly, Treg did not develop. Langerin is not only expressed in LCs but also in some dermal dendritic cells (dDCs). Langerin-positive dDCs repopulate within 10 days after depletion, whereas LCs are still absent. Langerin-DTR mice treated with DT 10 days before UVR and sensitization were still resistant to UVR-induced inhibition of contact hypersensitivity (CHS). Similarly, Treg did not arise. As in this setting only LCs but not Langerin-positive dDCs are absent, LCs appear to be essential for both the suppression of CHS and the induction of Treg by UVR. This supports the concept that LCs are more important for the downregulation than the induction of immune responses in the skin.

Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis.

OBJECTIVE: We previously demonstrated that CD4+,CD25+ regulatory T (Treg) cells are present in increased numbers in the synovial fluid (SF) of rheumatoid arthritis (RA) patients and display enhanced suppressive activity as compared with their peripheral blood (PB) counterparts. Despite the presence of these immunoregulatory cells in RA, chronic inflammation persists. The purpose of the present study was to investigate whether particular proinflammatory mediators that are associated with RA could abrogate CD4+,CD25+ Treg-mediated suppression. METHODS: Monocyte phenotype was determined by flow cytometry and cytokine levels by enzyme-linked immunosorbent assay. Magnetically sorted CD4+,CD25- and CD4+,CD25+ T cells derived from the PB and SF obtained from RA patients were stimulated alone or in coculture with anti-CD3 monoclonal antibody (mAb) and autologous antigen-presenting cells, in the absence or presence of anti-CD28 mAb or the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), or IL-7. RESULTS: Monocytes from the SF of RA patients displayed increased expression of HLA class II molecules, CD80, CD86, and CD40 as compared with PB-derived monocytes, indicating their activated status. Mimicking this increased costimulatory potential, addition of anti-CD28 mAb to cocultures of CD4+,CD25- and CD4+,CD25+ T cells resulted in reduced CD4+,CD25+ Treg-mediated suppression in both PB and SF. Furthermore, IL-7 and, to a limited extent, TNFalpha, both of which are produced by activated monocytes and were detected in SF, abrogated the CD4+,CD25+ Treg-mediated suppression. In contrast, IL-6 did not influence Treg-mediated suppression. CONCLUSION: Our findings suggest that the interaction of CD4+,CD25+ Treg cells with activated monocytes in the joint might lead to diminished suppressive activity of CD4+,CD25+ Treg cells in vivo, thus contributing to the chronic inflammation in RA.