Microbiota dictate T cell clonal selection to augment graft-versus-host disease after stem cell transplantation

• Published in: Immunity (Cambridge, Mass.) Vol. 57; no. 7; p. 1648
• Main Authors: Yeh, Albert C, Koyama, Motoko, Waltner, Olivia G, Minnie, Simone A, Boiko, Julie R, Shabaneh, Tamer B, Takahashi, Shuichiro, Zhang, Ping, Ensbey, Kathleen S, Schmidt, Christine R, Legg, Samuel R W, Sekiguchi, Tomoko, Nelson, Ethan, Bhise, Shruti S, Stevens, Andrew R, Goodpaster, Tracy, Chakka, Saranya, Furlan, Scott N, Markey, Kate A, Bleakley, Marie E, Elson, Charles O, Bradley, Philip H, Hill, Geoffrey R
• Format: Journal Article
• Language: English
• Published: United States 09-07-2024
• Subjects: Animals; Bayes Theorem; CD4-Positive T-Lymphocytes - immunology; Clonal Selection, Antigen-Mediated; Gastrointestinal Microbiome - immunology; Graft vs Host Disease - immunology; Graft vs Host Disease - microbiology; Hematopoietic Stem Cell Transplantation - adverse effects; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microbiota - immunology; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Stem Cell Transplantation - adverse effects; Transplantation, Homologous; stem cell transplant; T cell repertoire; microbiota T cells; CD4(+) T cell; histocompatibility; GVHD; microbiome; graft-versus-host disease
• ISSN: 1097-4180
• DOI: 10.1016/j.immuni.2024.05.018

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 closed genetic system within which donor T cells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient T cell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs. A subset of donor CD4
T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.