Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Gary A. Koretzky

Abstract

CD4+ T helper (Th) cells are essential components of the adaptive immune system that orchestrate the immune response by producing a distinct array of cytokines specific to each subset. Th17 cells, the IL-17 producing subset of the CD4+ Th cell family, are critical for host defense again extracellular pathogens, especially at barrier and mucosal sites. Dysregulation of Th17 cells, meanwhile, leads to the pathogenesis of a number of autoimmune and inflammatory diseases, and modulating the development and/or function of these cells for therapeutic purposes are of great interest. The conventional paradigm dictated that all Th17 cells differentiate from naïve CD4+ T cells at peripheral effector sites. Here, we identify a novel population of Th17 cells that acquire effector function during development in the thymus. These natural Th17 (nTh17) cells share the characteristic Th17-phenotype yet are poised to produce cytokines prior to antigen exposure in the periphery, thereby constituting a population distinct from peripherally induced Th17 (iTh17) cells. nTh17 cells show preferential usage of TCR genes, require expression of MHC class II specifically on the mTECs for selection, and arise independently of commensal microbiota. Thymic development of nTh17 cells requires signals distinct from its inducible counterpart. A hypomorphic TCR signaling mutant enhances nTh17 cell development while iTh17 cell generation is defective in these mice. nTh17 cells require CD28 costimulation and cytokines IL-6 and TGFbeta for thymic development; IL-1beta and IL-23 are dispensable in this process. Downstream of these signals, Akt is a key positive regulator controlling nTh17 cell development. Interestingly, nTh17 cells require mTORC2 activity but are independent of the mTORC1-ARNT/HIF1alpha axis whereas iTh17 cells have opposite developmental requirements, thus revealing the differential role of Akt and mTOR pathways in the regulation of these two distinct Th17 cell subsets. Finally, we find that nTh17 cells preferentially home to the lung suggesting a potential physiological niche for peripheral nTh17 cell localization and function. Taken together, our findings define a Th17 cell population of thymic origin that is distinct from conventional Th17 cells and functions at the interface of innate and adaptive immunity.

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