Memory CD4+ T cells are refractory to TGF‐beta‐mediated, retinoic acid‐enhanced conversion into Foxp3+ regulatory T cells by oral antigen

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Although it is well known that orally administered antigen can efficiently induce peripheral tolerance to prevent otherwise serious autoimmune diseases, most studies have failed to ameliorate the ongoing diseases by oral antigen. To clarify the cause of resistance to oral tolerance in subjects with an active autoimmune state, we focused on oral antigen‐induced generation of CD4+Foxp3+ regulatory T cells (Tregs) which play a crucial role in oral tolerance. Here, we show that Ag‐specific memory CD4+ T cells are refractory to oral antigen‐induced conversion into Tregs, whereas Tregs can easily be generated from naïve CD4+ T cells by oral antigen. We also show that Ag‐specific memory CD4+ T cells are inferior to naïve CD4+ T cells in TGF‐β‐mediated conversion into Tregs in vitro, although all‐trans retinoic acids (ATRA) can enhance the conversion of them. In addition, when we compared CD45RBlow or CD62Llowmemory phenotype(MP) CD4+T cells with CD45RBhigh or CD62Lhigh CD4+ naïve cells in TGF‐β‐mediated, ATRA‐enhanced conversion in vitro, MP CD4+ T cells were less succeptible to TGF‐β‐mediated Treg induction and were totally refractory to ATRA‐mediated enhancement of conversion. Altogether, these findings suggest that the refractoriness of memory CD4+ T cells to oral antigen‐induced conversion into Tregs can be the cause of unresponsiveness to oral tolerance in patients with active autoimmune diseases.