Elucidation of the Roles of TNFRSF Receptors in Cutaneous T Cell Responses
Regulatory T cells (Tregs) are closely related to Th17 cells and utilize aspects of the Th17-differentiation program for optimal immune regulation. In several chronic inflammatory human diseases, Tregs express IL-17A, suggesting that dysregulation of Th17-associated pathways in Tregs may result in either loss of suppressive function and/or conversion into pathogenic cells. The pathways that regulate the Th17 program in Tregs are poorly understood. We have identified two TNFRSF members, CD27 and OX40, to be preferentially expressed by skin-resident Tregs. Both CD27 and OX40 signaling suppressed the expression of Th17-associated genes from Tregs in a cell intrinsic manner in vitro and in vivo. However, only OX40 played a non-redundant role in promoting Treg survival. Tregs that lacked both CD27 and OX40 were defective in controlling inflammation, had reduced accumulation in both skin and SDLNs, and expressed high levels of IL-17A, as well as the master Th17 transcription factor, RORt. Finally, we found that CD27 expression was inversely correlated with Treg IL-17 production in skin of psoriasis and hidradenitis suppurativa patients. Taken together, our results suggest that TNFRSF members play both redundant and unique roles in regulating Treg plasticity.
We further explored how CD27 influences CD4+ effector (Teff) cells in inflamed tissues. Utilizing a murine model of inducible self-antigen expression in the epidermis, we elucidated the functional role of CD27 on auto-reactive Teff cells. Expression of CD27 on antigen-specific Teff cells resulted in markedly enhanced skin inflammation when compared to CD27-deficient Teff cells. CD27 signaling promoted the accumulation of cytokine-producing T cells in a cell-intrinsic fashion. Surprisingly, this costimulatory pathway had minimal effect on early T cell activation and proliferation. Instead, signaling through CD27 resulted in the progressive survival of Teff cells during the autoimmune response. CD27 did not appear to affect the intrinsic (mitochondrial) apoptosis pathway. Instead, CD27-deficient Teff cells expressed higher levels of active-caspase 8. Taken together, these results suggest that CD27 does not promote Teff cell survival by increasing expression of anti-apoptotic BCL2 family members but instead acts by preferentially suppressing the cell-extrinsic apoptosis pathway, highlighting a previously un-identified role for CD27 in augmenting autoreactive Teff cell responses.