The innate immune response is an ancient defense system made up of functionally distinct subsystems that have evolved to counter infection by microbial pathogens. A successful innate response promotes the secretion of cytokines and growth factors that shape the later pathogen-specific, or acquired immune response composed of B- and T-lymphocytes. While the role of type I interferons in the clearance of infectious agents is unquestionable, their role in the immune system in the absence of microbial presence is substantially less well understood. We had previously reported a dramatic increase in susceptibility towards autoimmunity in mice lacking the interferon-activated STAT1 transcription factor. Our recent research revealed a considerable contribution of the type I interferon system in the development of thymic epithelial cells that is likely to contribute to the development of various autoimmune disorders. Intriguingly, the interferon regulatory factors 3 and 7, two transcription factors controlling type I interferon production, have been studied exhaustively in innate immunity, but their potential contributions to the adaptive immune system have largely been left unexplored. Indeed, our recent studies revealed critical, but very distinct roles in lymphocyte development and function: we have already published on a novel and critical involvement of IRF7 and the type I interferon signaling system in the development and function of medullary thymic epithelial cells which are crucial in the prevention of autoimmunity. Our finding of IRF7 activation by RANKL gains additional significance due to the fact that thus far only PAMPs/pathogens were known to activate IRF7, but not any other cytokine. IFN? produced by medullary thymic epithelial cells (mTEC) ? a major source of IFN? in the thymus ? acts in an autocrine feedback loop to regulate mTEC proliferation and function. Our newest preliminary date contained within this application revealed that IRF3, too, plays a critical role in the adaptive immune system that impacts the ability of CD4+ T cells to be controlled by Treg cells and alters the ability of CD4+ T cells to trigger autoimmunity. The most important mechanistic aspect behind this observation is our discovery that nave T cells fail to differentiate into Th17 cells in the absence of T cell-intrinsic IRF3, both in vitro and in vivo. We thus exposed that both IRF3 and IRF7 harbor a T cell intrinsic function rather than simply affecting stromal cell/APC function. We therefore propose the generation and basic characterization of conditionally targeted IRF7 mice to continue to investigate the unique, tissue-specific functions of IRF7 in the adaptive immune system, (particularly with respect to the development of T cells and their responses to antigens and/or pathogens. It should also be noted that many of the IRF3/7 contributions we observed in the adaptive immunity can be separated from the type I interferon system). These animal will not only allow us to shed light onto novel cell-type specific roles of IRF7 contributing to thymic and peripheral T cell development and function, but also elucidate novel roles for IRF3 and IRF7 in the adaptive immune system beyond their well-established function as interferon regulators during innate immune events.

Public Health Relevance

More than 23 million Americans (75% of them women) suffer from autoimmune disease, and many more from a variety of other immune disorders (allergies, immune deficiencies, etc.). Our discovery that thymic interferon production is a crucial determinant in the development of thymic epithelial cells which regulate the elimination or activation of autoreactive T cells already provided new insights into the function of this clinically widely used cytokine outside the infectious disease arena. Our current work focusing on the roles of the interferon regulatory factors 3 and 7, two transcription factors that have been studied exhaustively in innate immunity, but whose function in adaptive immunity has largely been left unexplored, has revealed critical, but very distinct roles in lymphocyte development and function (this is an interesting contrast to their contributions to innate immunity, where these IRFs fulfill an almost identical, but temporarily offset, function. As such, our preliminary data and the proposed work will address an important and unexplored area of the adaptive immune system.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Research Grants (R03)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Prabhudas, Mercy R
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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