Retinoic acid regulates donor myeloid-derived suppressor cell and colonic dendrite cell reconstitution after allogeneic hematopoietic stem cell transplantation in mice

Abstract

Graft-versus-host disease (GVHD) remains a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HSCT). Donor hematopoietic progenitor cells reconstitute the recipient’s immune system after transplant, and newly generated donor-derived immune cells actively participate in propagating alloimmunity. Retinoic acid (RA) has well-known effects on the differentiation and proliferation of myeloid progenitor cells. We hypothesized that RA influences the reconstitution of some donor-derived myeloid cell populations after allogeneic HSCT. In a C57BL/6 into Balb/c murine allogeneic bone marrow transplantation (BMT) model, we found that Gr1+CD11b+CD84+F4-80- myeloid-derived suppressor cells (MDSCs) accumulated in the spleen of recipient mice early after BMT. Notably, the absolute number of MDSCs was significantly reduced in RA-treated mice compared with DMSO-treated mice. Furthermore, MDSCs isolated from RA-treated recipient mice showed decreased immunosuppressive function in mixed lymphocyte reactions (MLRs). Bulk RNA-sequencing (RNA-seq) revealed that RA treatment alters transcriptional programs involving Wnt signaling and the CCL2-CCR2 axis in MDSCs. We found that adding RA to the MDSC culture promotes the differentiation of Ly6C-Ly6G+ granulocytic MDSCs. Thus, enhancing RA signaling causes both quantitative and qualitative changes of MDSCs after allogeneic HSCT. Recent studies have demonstrated an important role of donor intestinal CD103+ dendrite cells (DCs) in propagating GVHD. We found that RA-treated recipient mice had significantly increased colonic CD103+ DCs compared with DMSO-treated mice. On the contrary, vitamin A deficiency was associated with a significant reduction in the percentage and absolute number of CD103+ DCs. To study the effects of RA on DCs in vitro, BM cells were cultured in the presence of GM-CSF. There was a significant increase in the percentage of CD11c+CD103+ mucosal DCs in cultures exposed to RA. Furthermore, RA-exposed DCs exhibited increased MHC-II expression and enhanced T-cell stimulatory capacity. In summary, our study demonstrated that RA participates in regulating donor MDSC and colonic CD103+ DC reconstitution after allogeneic HSCT. Therapeutic modulation of RA signaling or its downstream pathways may represent a strategy to limit alloimmunity and improve transplant outcomes.