The innate immune response is an ancient defense system made up of functionally distinct subsystems that have evolved to counter infection by microbial pathogens. The innate response is generally not antigen-specific, and is composed of the interferon (IFN) system, as well as cell-based anti-pathogen countermeasures that serve to restrict the replication of pathogens early in infection. 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. We recently discovered that IFN? produced by medullary thymic epithelial cells (mTEC) - a major source of IFN? in the thymus - acts in an autocrine feedback loop that appears to regulate mTEC maturation. Our most recent studies revealed a considerable contribution of the type I interferon system to the development of regulatory T cell that is likely to contribute to the development of various autoimmune disorders. We demonstrated a novel and critical involvement of IRFs and the type I interferon signaling system in the development and function of both natural and induced regulatory T cells which are crucial in the maintenance of peripheral tolerance and the prevention of autoimmunity. We therefore propose to investigate the unique functions of IRFs, IFN?/? and STAT1 in the processes of Treg cell development and function.
In Aim 1 we will investigate the role of STATs and IFN?/? signaling components in the development of natural and induced Treg cells. We will determine whether T cell intrinsic requirements for these factors exist, or whether their impaired development results from an impaired thymic architecture. We will further investigate the mechanism why STAT1-deficient FoxP3+ cells fail to suppress effector T cells, and whether interferon can alter the conversion of conventional effector T cells into induced Treg cells. Our pilot experiments also revealed that IRF3-deficiency leads to increased natural Foxp3+ Treg cell numbers with progressive age. Unexpectedly, while natural Treg cells were increased in IRF3-/- mice, we observed a concomitant defect in the generation of induced (adaptive) Foxp3+ Treg cells. We noted that IRF3-/- natural Treg cells function normally, but strikingly, conventional IRF3-/- CD4+T cells are resistant to suppression by Treg cell. We will therefore determine in Aim 2 whether IRF3 is required in a T cell-intrinsic manner, and whether the failure of IRF3-deficient CD4+ T cells to respond to Treg cell-mediated suppression is due developmental alteration that occurred due to IRF3-deficiency in other thymic cell populations. The anticipated results will not only shed light onto a novel aspect of Treg cell development but also elucidate an additional biological role of type I interferons. Even though interferons are being used clinically to treat autoimmune diseases such as Multiple Sclerosis, the underlying mechanism is poorly understood. The proposed studies will extend our understanding of the contributions of IRFs and type I interferons in the development of Treg cells that are essential in the maintenance of self-tolerance.
More than 23 million Americans (75% of them women) suffer from autoimmune disease. Our discovery that the type I interferon system is a crucial determinant in the development of regulatory T cells which regulate the elimination or activation of autoreactive T cells provides new insights into the function of this clinically widely used cytokine outside the infectious disease arena.
|Otero, Dennis C; Fares-Frederickson, Nancy J; Xiao, Menghong et al. (2015) IFN-? Selectively Inhibits IL-2 Production through CREM-Mediated Chromatin Remodeling. J Immunol 194:5120-8|
|Otero, Dennis C; Baker, Darren P; David, Michael (2013) IRF7-dependent IFN-? production in response to RANKL promotes medullary thymic epithelial cell development. J Immunol 190:3289-98|