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4776 Donor T-Derived Memory Progenitors Differentiated into CD103+/- CXCR6+CD4+ Tissue-Resident T Cell Subsets Driven Cutaneous Chronic Graft-Versus-Host Disease

Program: Oral and Poster Abstracts
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

Xiaohui Kong, PhD1,2*, Bixin Wang, MD, PhD1*, Xiwei Wu, PhD, MD3*, Weijia Fu1*, Qinjian Li1*, Moqian Zheng1,2*, Raju Pillai, MD4*, Ryotaro Nakamura, MD5, Paul J. Martin, MD6 and Defu Zeng, MD1,2

1Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, Beckman Research Institute of City of Hope, Duarte, CA
2Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Comprehensive Cancer Center, Duarte, CA
3Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Duarte, CA
4Department of Pathology, City of Hope National Comprehensive Cancer Center, Duarte, CA
5Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
6Fred Hutchinson Cancer Center, Seattle, WA

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.

*signifies non-member of ASH