DESCRIPTION (provided by applicant): The immune system responds to infection with a complex interplay of immune cells and secreted factors aimed at eliminating the intruding pathogen and repairing damaged tissue. Innate lymphocytes, which include NK cells, NKT cells, T cells, and the newly discovered innate lymphoid cells (ILCs), are a fascinating and relatively understudied subset of immune cells that function at the interface of innate and adaptive immune responses. My goal is to establish independent research program focused on understanding the molecular pathways that regulate effector responses by innate lymphocytes during infection. During my postdoctoral training, I discovered a novel signaling pathway involving the transcription factors Zbtb32 and Blimp-1 that critically regulates anti-viral responses by NK cells1. As an independent faculty researcher, I plan to continue my investigation of how Zbtb32 regulates anti-pathogen responses by innate lymphocytes. Specifically, the studies proposed in this K22 application aim to: (1) determine whether Zbtb32 and Blimp-1 physically interact in NK cells and whether Zbtb32 influences the suite of genes targeted by Blimp- 1 for transcriptional repression; and (2) explore whether Zbtb32 regulates anti-viral immune responses by Type 2 ILCs during influenza infection in vivo. Given the remarkable range of diseases regulated by innate lymphocytes, including viral, bacterial, and helminth infections, and allergic and autoimmune diseases, the proposed studies will have important applications in the development of new therapies, vaccines, and diagnostic tests for a wide variety of human illnesses. Moreover, support from this K22 award would provide me with key time and resources to successfully transition into a tenure-track faculty position and to acquire the knowledge and data I will need to launch a productive and sustainable independent research career.

PUBLIC HEALTH RELEVANCE: Innate lymphocytes such as NK cells and innate lymphoid cells are important mediators of immune responses during infection, allergy, and autoimmunity. My research is aimed at defining the molecular pathways and signals that regulate innate lymphocyte function during infection. By gaining a better understanding of how cells of the innate immune system mount protective immune responses against pathogens, or damaging immune responses in the context of allergy and autoimmunity, we can develop more effective therapies and vaccines to treat a wide range of infectious and non-infectious human diseases.