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

Authors

Xinlei Li, Jianwei Zheng, Dian Zhou, Rachel Limpert, Brian Taylor, Linlu Tian, Xue-Zhong Yu, William R Drobyski, Xiao Chen

Published in

Frontiers in immunology. Volume 17. Pages 1599346. Epub Sep 22, 2026.

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.

PMID:
42840641
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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