Regulatory T cell derived inhibitory cytokines and regulation of anti tumor immunity
Regulatory T cells (Tregs) play a crucial role in the maintenance of self tolerance and prevent overt immune responses during infection. One of the primary mechanisms of immune regulation by Tregs is via secretion of inhibitory cytokines (IL 10, IL 35, and TGF b) and activated Tregs producing these inhibitory cytokines are highly enriched in the tumor microenvironment (TME) However, it is yet unclear whether intratumoral Tregs preferentially utilize one regulatory mechanism over others in the TME. We have previously demonstrated that Treg derived IL 35 regulate anti tumor immunity by promoting the inhibitory receptor expression in CD8+ TILs. As induction of a dysfunctional state known as T cell exhaustion in tumor infiltrating T cells presents a barrier to effective cancer immunotherapy, it is imperative to understand the mechanism of Treg derived inhibitory cytokine mediated induction of T cell exhaustion and the developmental relationship between subpopulations of effector Tregs in the TME. In Chapter 3, I demonstrate that IL 10+ and IL 35+ Tregs are not distinct, stable subsets of Tregs, and intratumoral Tregs exhibit the environmentally inducible adaptive plasticity of the IL 10 and IL 35 expression. In Chapter 4, I show that Treg derived IL 10 and IL 35, despite the difference in their receptors and the downstream signal transduction, commonly target the BLIMP1 IR axis in CD8+ T cells to directly promote a dysfunctional state of T cells. Furthermore, in Chapter 5, I present an alternative function of Treg derived Ebi3 that is independent of the IL 12 cytokine family and a novel cytokine complex composed of IL 10 and Ebi3 produced by activated Tregs. Treg derived Ebi3 may have a broader physiological role than previously appreciated, and a comprehensive understanding of such unconventional role of Ebi3 in modulating immune responses is crucial to develop a novel therapeutic approach to target Ebi3 rationally. In addition to my thesis study, Appendix A lists the publications that I have contributed, as well as additional academic achievements such as awards and honors received at external conferences.