Regulatory T cell heterogeneity and function during influenza A virus infection

Abstract

Regulatory T-cells are a subset of CD4+ T-cells important for preventing autoimmunity, suppressing immune responses, and promoting tissue repair. Although originally thought of as a homogenous population, recent studies indicate that Tregs are diverse in their phenotype and function. With the introduction of single-cell RNA-seq, the heterogeneity of Tregs could be evaluated at enhanced resolution. Quiescent central Tregs that circulate through the secondary lymphoid organs can undergo activation that differentiates them into activate effector Tregs. From there, Tregs can enter into tissues and undergo further phenotypic diversification depending on the tissue. While steady state Tregs have been extensively profiled in recent years, there is limited understanding of how infection alters heterogeneity of Tregs within the affected tissue. Additionally, genetic tools to study the function of particular Treg subsets are lacking and need improvement. In the studies described here, I identified distinct Treg subsets that respond to the lungs during influenza A virus infection and interrogated their function using a novel transgenic mouse model. During influenza A virus infection, there are two waves of Tregs that infiltrate the lungs: interferon stimulated gene-expressing Tregs (ISG-Tregs) and tissue repair Tregs (TR-Tregs). These subsets are distinct in their kinetics, transcriptional phenotype, and TCR repertoire. To study the function of unique Treg subsets during infection, I designed the Foxp3-iDTR mouse model that allows for tracking and depletion of transcriptionally unique Treg populations. The results of my thesis studies will further our understanding of Treg heterogeneity during infections and provide a unique new mouse model for dissecting the fate and function of distinct Treg subsets.