同种异体T细胞扩增是移植物抗宿主病(GVHD)的主要决定因素,目前的教条规定,这是由供体和受体之间的组织相容性抗原差异驱动的。该范例代表了一个封闭的遗传系统,在该系统中,供体T细胞与肽-主要组织相容性复合物(MHCs)相互作用。尽管由于T细胞库的稀疏性,克隆询问仍然具有挑战性。我们使用小鼠干细胞移植系统中的供体和受体T细胞受体(TCR)频率开发了贝叶斯模型,以定义跨遗传相同的供体-受体对的T细胞克隆的有限的共同扩增。供体CD4+T细胞克隆型的子集在相同的受体中差异扩增并且是微生物群依赖性的。微生物群特异性T细胞增强了GVHD的致死率,并且可以在同种反应性反应期间靶向胃肠道上皮呈递的微生物抗原。微生物群作为同源抗原的来源,有助于克隆型T细胞扩增和GVHD的诱导,而与供体-受体遗传学无关。
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.