Advisory Committee Chair
Casey T Weaver
Advisory Committee Members
Charles O Elson III
Hui Hu
Robinna G Lorenz
Craig L Maynard
Document Type
Dissertation
Date of Award
2022
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Heterogeneity in phenotype and function of Treg cells is becoming increasingly appreciated, especially in the context of creating potent Treg cell–based therapeutics in the treatment of inflammatory bowel disease. One of the barriers to developing such therapeutics is the limited understanding of the signals that play a role in the development of Treg cell subsets. Here, we found STAT3 signaling to be enriched in induced IL-10 competent Treg (iTreg) cells in the colon. Through the development of a new in vitro system, we found that STAT3 was required for proper development of IL-10 competent iTreg cells and that IL-2 regulated the activation of STAT3 in this population. Early in iTreg development, STAT3, directly downstream of IL-2 signaling, primes Treg cells for effector competency in both a cis and trans fashion by shaping chromatin landscape around Il10 and by negatively regulating the expression of the transcriptional repressor bHLEH40. These results are particularly relevant in the context of IL-2 muteins that are being developed as therapeutics, as we identified one reagent that did not activate STAT3 downstream of IL-2 and, therefore, had differential effects on Treg subsets in vivo. Due to its potent effects on T conventional and T regulatory cells, IL-2 is dynamically and tightly regulated in vivo. Currently, there is a lack of understanding of what signals dictate IL-2 production and consumption by CD4 T cells. Herein, we show that death receptor 3 (DR3), a tumor necrosis factor receptor superfamily member (TNFRSF), dynamically regulates both IL-2 production by conventional CD4+ T cells and IL-2 coniv sumption by Treg cells. We found that DR3 is expressed early in iTreg development and that DR3 stimulation enhances Treg IL-10 and effector competency by co-opting the aforementioned IL-2–pSTAT3 signaling axis. We show that DR3 stimulation has broad implications for immune cell subsets in a variety of tissues, as DR3 stimulation protected from disease in the murine model of multiple sclerosis (EAE). These data highlight the therapeutic potential of combining reagents that alter Treg cell sensitivity to IL-2 with IL- 2 muteins that signal specifically on Treg cells in vivo.
Recommended Citation
Dean, Emma C., "IL-2-Mediated STAT3 Activation Controls Effector T Regulatory Cell Development" (2022). All ETDs from UAB. 498.
https://digitalcommons.library.uab.edu/etd-collection/498
