Early-Life Microbes Prevent Autoimmune Diabetes by Upregulating PD-1 on T Cells
openNIDDK - National Institute of Diabetes and Digestive and Kidney Diseases
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.
Up to $50K
health research