Differential role of all-trans retinoic acid in promoting the development of CD4⁺ and CD8⁺ regulatory T cells

It is known that ATRA promotes the development of TGF-β-induced CD4⁺Foxp3⁺ iTregs, which play a vital role in the prevention of autoimmune diseases; however, the role of ATRA in facilitating the differentiation and function of CD8⁺Foxp3⁺ iTregs remains elusive. Using a head-to-head comparison, we found that ATRA promoted expression of Foxp3 and development of CD4⁺ iTregs, but it did not promote Foxp3 expression on CD8⁺ cells. Using a standard in vitro assay, we demonstrated that CD8⁺ iTregs induced by TGF-β and ATRA were not superior to CD8⁺ iTregs induced by TGF-β alone. In cGVHD, in a typical lupus syndrome model where DBA2 spleen cells were transferred to DBA2xC57BL/6 F1 mice, we observed that both CD8⁺ iTregs induced by TGF-β and ATRA and those induced by TGF-β alone had similar therapeutic effects. ATRA did not boost but, conversely, impaired the differentiation and function of human CD8⁺ iTregs. CD8⁺ cells expressed the ATRA receptor RAR and responded to ATRA, similar to CD4⁺ cells. We have identified the differential role of ATRA in promoting Foxp3⁺ Tregs in CD4⁺ and CD8⁺ cell populations. These results will help to determine a protocol for developing different Treg cell populations and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation.