Abstract
Allogeneic Tcell 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 Tcells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the Tcell repertoire. We developed a Bayesian model using donor and recipient Tcell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of Tcell clones across genetically identical donor-recipient pairs. A subset of donor CD4+ Tcell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific Tcells 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 Tcell expansion and the induction of GVHD independent of donor-recipient genetics.
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