Specialization of regulatory T cell-mediated immune regulation during Toxoplasma infection

University Of California, San Diego, La Jolla CA

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Abstract

IFN?-driven type I T cell (Th1) immunity provides host defense against intracellular parasites such as Toxoplasma gondii (T. gondii) but can also cause deleterious inflammatory responses and tissue damage in the absence of proper regulations. Regulatory T (Treg) cells, a specialized immune population, are known for their role in maintaining immunological tolerance. Mounting evidence has suggested that Treg cells come in ?different flavors? phenotypically and functionally. Specifically, a population of T-bet+ Th1-Treg cells was shown to play a crucial role in limiting Th1 inflammation during T. gondii infection. The goal of this study is to define the precise cellular and molecular mechanisms underlying Treg cell-mediated regulation of Th1 immunity in both physiological and T. gondii infection settings. By establishing novel mouse models which could allow us to specifically deplete T-bet+ Treg cells as well as Klrg1+Gata3+T-bet- Treg cells in a temporally controlled manner, we will able to examine the potential beneficial vs detrimental outcomes of ablating two distinct Treg cell subsets during different phases of T. gondii infection. Next, we will identify key downstream effector molecules critical for Treg cell-mediated Th1 regulation. In particular, with newly acquired KO and conditional KO mouse models as well as retroviral experimental approaches, we will explore and identify potential effector mechanisms by which Treg cells control IFN?-mediated Th1 immunity. Finally, by using mice with ablated IL-27 and its receptor (IL-27R?) as well as other Stat1 activating cytokines (and their receptors) in defined immune cell populations, we will elucidate the environmental impact on the immune regulation mediated by Treg cells as well as other T cell subsets with regulatory properties such as IL-10-producing Foxp3- T-regulatory 1 (Tr1) cells and IL-27-producing T cells during T. gondii infection. Results obtained from this study will provide mechanistic insights into Th1-Treg cell-mediated control of host-pathogen interactions. Ultimately, our study will further extend our fundamental knowledge of this functionally specialized Treg cell subset in regulating human health and disease.