Program: Oral and Poster Abstracts
Session: 701. Experimental Transplantation: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Translational Research
Session: 701. Experimental Transplantation: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Translational Research
Monday, December 9, 2024, 6:00 PM-8:00 PM
Cutaneous chronic graft versus host disease (cGVHD) is the major clinical manifestation of cGVHD patients. Tissue-resident memory T (Trm) cells and TCF1+ T progenitors locally in GVHD target tissues play important roles in maintaining GVHD. However, the mechanisms regulating TCF1+ progenitor differentiation into Trm in the skin remain largely unknown. In the current studies, with cGVHD murine models (C57BL/6 donors and BABL/c recipients) and humanized models of human HLA-A2-DR4- PBMC to MHC-/-HLA-A2+DR4+ NSG mice, we observed with flow cytometry analysis that most (>90%) of the injected donor CD4+ T cells in the skin tissues were CD69+ Trm, and the TCF1+ progenitors were less than 4%, which was markedly lower than in the liver and lung (>20%). The majority of Trm cells in the cGVHD skin were CD103+CXCR6+Foxp3- conventional CD4+ T cells that produce large amount of pro-inflammatory IFN-γ and GM-CSF, while CD103+ Trm cells in the skin of non-GVHD recipients were mostly Foxp3+ Treg cells. Genetic deficiency of T-bet, BHLHE40, STAT3 or BATF in the injected donor T cells markedly ameliorated skin cGVHD, all associated with lower numbers of CD103+ Trm cells and lower production of IFN-g/GM-CSF. Results were similar when skin cGVHD was greatly reduced by post-transplantation treatment with cyclophosphamide (PTCY) in murine models. In addition, scRNA-seq analysis of blood and skin T cells from GVHD patients in a public dataset showed that ~90% blood T cells express stemness related marker Tcf7 and large proportions of skin T cells (>95%) express terminally differentiated markers such as Cxcr6. Taken together, our results suggest that the differentiation of TCF1+ T progenitor cells into Trm cells in the skin is regulated by the T-bet/BHLHE40 axis and the TCR/STAT3/BATF axis. Although Trm cells are differentiated from TCF1+ T progenitor cells in the skin, the TCF1+ T progenitor cells in blood may play an important role in replenishing TCF1+ T progenitor cells in cGVHD target tissues.
Disclosures: Nakamura: Maat Pharma: Research Funding; Helocyte: Research Funding; Mitarisan: Research Funding; Blue Bird (ended): Consultancy; Sanofi: Consultancy; Ono Pharmaceutical: Consultancy; Pfizer: Consultancy; Omeros (ended): Consultancy. Martin: Procter and Gamble: Current equity holder in publicly-traded company; AltruBio: Research Funding; Talaris: Other: honoraria for endpoint adjudication; Pfizer: Other: honoraria for data and safety monitoring; Moderna: Current equity holder in publicly-traded company.
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