Microbiota-Specific T Cells Contribute to Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

Background: Allogeneic T-cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a fixed genetic system within which donor T cells int...

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Published in:Blood 2023-11, Vol.142 (Supplement 1), p.345-345
Main Authors: Yeh, Albert C, Koyama, Motoko, Waltner, Olivia, Minnie, Simone A, Boiko, Julie, Shabaneh, Tamer B, Takahashi, Shuichiro, Zhang, Ping, Ensbey, Kathleen, Schmidt, Christine, Legg, Samuel, Sekiguchi, Tomoko, Nelson, Ethan, Bhise, Shruti, Stevens, Andrew, Goodpaster, Tracy A, Chakka, Saranya R., Furlan, Scott N., Markey, Kate A., Bleakley, Marie, Elson, Charles O, Hill, Geoffrey R
Format: Article
Language:English
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Summary:Background: Allogeneic T-cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a fixed genetic system within which donor T cells interact with recipient-derived peptide-MHC complexes. However, the current model does not account for potential cognate interactions between donor T cells and microbe-derived antigen presented by the recipient. Prior studies in healthy patients have demonstrated the existence of circulating αβT cells targeting common bacterial species in the gastrointestinal (GI) tract. Whether microbe-specific T cells derived from the donor graft impact GVHD outcomes has not been studied. We tested the hypothesis that the recipient GI microbiota serve as a source of cognate antigen, contributing to clonotypic donor T-cell expansion and induction of GVHD. Methods: Functional studies utilized allogeneic stem cell transplant models in murine systems including both matched (Marilyn Tg to B6 male) and mismatched (B6 to B6D2F1) transplants as well as inducible MHCII knockout mice. Microbiota-specific transgenic T cells (MSTCs) targeting commensal flagellin (CBir1) and vendor-specific microbiome (segmented filamentous bacteria - SFB) in the context of I-A(b) were incorporated as part of the donor graft. Mechanistic studies utilized flow cytometry, cytokine stimulation and profiling, single-cell RNA sequencing, gene set enrichment analysis, NFAT-GFP T-hybridoma reporters, live-cell imaging (xCelligence RTCA eSight), and tissue analysis with RNA in-situ hybridization (ISH). Results: MSTCs lethally augmented GVHD when given as part of the donor graft in respectively colonized recipients. Taconic B6 male recipients (SFB-bearing) developed lethal GVHD when both donor Marilyn (Allo) Tg T cells and SFB T cells were introduced, but not when either transgenic T cell was introduced alone ( Figure A, p
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2023-178773