Propagation of graft vs. host disease through CD4+ T-cell cognate recognition of gastrointestinal microbiota

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PROJECT SUMMARY/ABSTRACT This proposal presents a five-year research career development program focused on the study of T-cell reconstitution following hematopoietic stem cell transplantation (HSCT) and how graft-vs-host disease (GVHD) can be shaped by clonotypic response to microbiota. The candidate is currently an Instructor of Medicine at the University of Washington and Research Associate at the Fred Hutchinson Cancer Research Center. This proposal builds on the candidate’s previous research and clinical experience by providing advanced training in two domains of expertise represented by his mentor team of Dr. Geoffrey Hill (GVHD in HSCT) and Dr. Philip Bradley (computational modeling of the T-cell response). The proposed experiments and didactic work will provide the candidate with a unique set of cross-disciplinary skills that will enable his transition to independence as a physician scientist in T cell mediated immunity in HSCT. T-cells play a fundamental role in the pathogenesis of GVHD which remains a major barrier for the successful application of HSCT for a wide range of benign and hematologic malignancies. GVHD involvement of the gastrointestinal (GI) tract remains a major cause of morbidity and mortality. The composition of the GI microbiome is associated with onset and severity of GVHD, though current understanding of how specific microbial species contribute to GVHD pathogenesis remains largely correlative with limited mechanistic insights. While the microbiome acts as a major source of cognate antigen for T cells, little is known about how anti-microbial TCRs may contribute to pathology in this setting. Part of the difficulty in parsing out the alloreactive response from immune surveillance on a clonal level includes the vast combinatorial diversity of αβ TCRs, the high prevalence of low copy number TCRs in any given donor pool, and sampling limitations. The foundation of this proposal is based on preliminary studies using a novel computational algorithm to identify expanded donor TCRs that are not constrained by donor and host genetics, but rather appear to be influenced by commensal microbes. How exactly these anti-microbial TCRs might function in the post-transplant context and its physiological relevance to GVHD are questions that this proposal begins to address. More specifically, the aims of this proposal are to 1) Validate computationally identified anti-microbial CD4+ TCRs in an scRNA seq platform and define cellular phenotypes in relation to compartment localization, 2) Reconstruct computationally identified CD4+ TCRs and determine antigenic specificity through genomic screening, and 3) Dissect the functional role of identified anti-microbial CD4+ TCRs on the propagation of acute graft-vs-host disease. The scientific objective of this proposal is to examine the drivers of clonotypic T-cell expansion following allogeneic stem cell transplant and assess how the pathogenesis of GVHD is coupled to microbial surveillance.