Nel, H.J., Ruscher, R., Boks, M., Thomas, R., and O'Sullivan, B. (2016) RelB-deficient dendritic cells have increased retinoic acid dehydrogenase activity and promote regulatory T cell differentiation in mice and humans. European Journal of Immunology, 46. 3362. p. 821.

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Abstract

Peripherally-derived Foxp3+ regulatory T (pTreg) cell generation from naïve T cells in the TGF-β-enriched intestinal environment depends on specialized dendritic cells (DCs). RelB-deficient mice have an increased proportion of Treg cells in the spleen despite their thymic atrophy and lack of lymph nodes and Peyer´s patches. The mechanism by which RelB influences pTreg is incompletely understood. We demonstrate in RelB-/- mice, that antigen-exposed RelB-/- DCs induce significantly more Tregs from adoptively-transferred CD4+CD25- precursors than RelB+/- mice. This was recapitulated in vitro. Treg induction was TGF-β- and retinoic acid (RA)-dependent. RA-metabolizing Raldh2 enzyme expression and ALDH activity were increased in RelB-/- relative to RelB+/- splenic DCs. In naïve mice, these ALDH+ DCs developing in the absence of RelB generated pTreg cells in the spleen in the context of high TGF-β production. To determine the relevance to immunotherapy, we compared human monocyte-derived DCs generated in the absence or presence of calcitriol, a selective suppressor of RelB. Similar to RelB-/- DCs, ALDH activity, ALDH1A2 and RA-responsive transcription factors RARA and RXRA expression were increased and LPS-induced costimulatory molecule expression was decreased in calcitriol-modified human DCs. In allogeneic mixed lymphocyte cultures, T cell proliferation decreased and IL-10+ regulatory T cells increased in response to calcitriolmodified, relative to untreated DCs. These data indicate that RelB deficiency or pharmacological inhibition promotes RA metabolism in DCs and RA- and TGF-β-dependent induction of regulatory T cells and support clinical application of DC targeting with RelB inhibitor and antigen.

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