Characterization of the regulatory TCR repertoire in the context of infection, inflammatory disease, and tumor microenvironment

Abstract

Abstract Regulatory T cells (Tregs) are key negative regulators of the immune system. Conventional T cells use their T cell receptor (TCR) to direct their effector function against specific targets. While much is known about the role of Tregs in their microenvironment, whether Tregs require this TCR specificity to elicit their effector functions is not clear. If so, Treg-specific antigens are also undefined. Investigation of the TCR repertoire can help to answer these questions as it provides insight into the degree of antigen recognition T cells experienced during a response. Since Tregs have been implicated in infection, autoimmunity, allergy, and cancer, we have chosen to characterize the Treg TCR repertoire in murine models for influenza, type I diabetes, asthma, neuroblastoma, and non-small cell lung carcinoma. Using an algorithm generated in our lab, TCRdist, we analyzed features of the TCR repertoire such as clonal expansion, TCR diversity, and V and J region biases. Our preliminary data show lung Tregs from asthmatic mice display the greatest antigen specificity while Tregs in influenza and neuroblastoma have minimal specificity based on clonal expansion and enrichment of TCR motifs. Additionally, we have identified Treg receptors that occur in more than one disease type. These data suggest that Treg TCR-dependency is condition-specific and may be determined by the local tissue as a pathological antigen. Future studies include associating these differences in the repertoire with TCR signaling and Treg functional capacities. Understanding the antigen-specificity of Tregs and identifying highly effective Tregs across diverse diseases can provide opportunities to develop broadly applicable, targeted therapeutics.