Early-Life Microbes Prevent Autoimmune Diabetes by Upregulating PD-1 on T Cells

About This Grant

Project Summary: Type 1 diabetes (T1D) is a chronic autoimmune disease that affects millions globally, and the incidence of T1D is increasing. Early-life disruptions of the gut microbiome have long-lasting impacts on the risk for developing type 1 diabetes (T1D), yet how the composition of the early-life microbiota contributes to T1D and whether manipulating it can prove therapeutically beneficial remains largely unexplored. To address this gap, we created a gnotobiotic model of the early-life microbiome, composed of a simple consortium of 9 culturable bacteria (PedsCom) that dominate the early-life microbiome of diabetes-protected animals. We found that PedsCom microbes confer protection from developing type 1 diabetes (T1D) in NOD mice. Importantly, PedsCom-mediated T1D protection is dependent on PD-1 signaling, as PD-1 blockade in PedsCom mice abrogates T1D protection. Remarkably, this PD-1-based protection from developing T1D is completely dependent on early-life colonization of NOD mice by PedsCom, thereby demonstrating a critical time window in which specific commensal microbes induce tolerance. The goal of this proposal is to identify mechanisms by which the early-life microbiome can modulate the immune response to inform microbiome-based therapeutics to prevent T1D in high-risk patients. To investigate immunomodulatory mechanisms of early-life microbes, we are integrating the innovative PedsCom gnotobiotic model of the early-life microbiome with key immunologic techniques, including high- dimensional spectral flow cytometry and single-cell RNA sequencing. In Aim 1, I will determine the degree to which PedsCom-induced PD-1+ T cells are anergic, hypofunctional, and islet-autoreactive. In Aim 2, I will establish whether PedsCom enhances PD-1 expression on T cells during specific early-life developmental windows. In Aim 3, I will determine whether specific PedsCom microbes are sufficient to induce PD-1 and restrain T1D in the context of a complex microbiome. During this fellowship, these investigations will diversity and strengthen my technical laboratory skills, expand my ability for experimental design and computational analysis, and enhance my scientific writing and communication skills. I will complete this fellowship at the University of Pennsylvania, in association with the Children’s Hospital of Philadelphia, both of which offer programs, courses, meetings, and structured mentorships that will aid my career development. In addition, I will take advantage of opportunities offered by the Immunology Graduate Group at Penn to improve my abilities as an educator through teaching programs and mentoring younger students. With these resources available, I will investigate the fundamental and clinically relevant questions in this proposal to gain the skills necessary to become an impactful scientist in an academic institution.