Roles and regulation of tissue resident CD8 T cells during a persistent viral infection

SUMMARY Sustained viral infections are characterized by a long-term equilibrium between the pathogen and the immune system that is enabled by adaptations of immune cells that attenuate selected functions. This equilibrium keeps the pathogen in check while minimizing immunopathology. Thus, studying the mechanisms that naturally evolved to allow adaptation of immune cells during sustained infections has great potential to uncover fundamental aspects of immune regulation that could be exploited to treat both infectious and non-infectious diseases. The above concept is illustrated by the discovery of exhausted CD8 T cells (TEX) as a distinct differentiation fate that is maintained by a stem-like progenitor subset (TEX-STEM), which is mostly restricted to lymphoid tissues and gives rise to all other TEX populations. Notably, these findings were originally made in mice chronically infected with lymphocytic choriomeningitis virus (LCMV) and then extended to many human viral infections, cancer, and autoimmune diseases. Following the same steps, we and others have recently taken advantage of the LCMV mouse model to study immune adaptations in the gastrointestinal (GI) tract. We revealed that the persistent LCMV isolate, Clone 13 (Cl13), productively replicates in the intestinal lamina propria (LPL), but not in the intestinal epithelium, and that this infection is associated with enhanced intestinal permeability to small molecules and increased susceptibility to chemically and bacterially induced colitis. We also uncovered that, during chronic LCMV infection, Type I interferons (IFN-I) promote tissue-associated virus- specific CD8 T cells (hereafter refer as T resident cells TRC) while preventing the emergence of TEX-STEM cells in intestinal tissues. Importantly, both IFN-I and CD8 T cells were essential for the hyper-permeability and enhanced colitis observed after LCMV Cl13 infection. Our overall goal is to leverage our previous studies to uncover the basic biology of tissue-resident CD8 T cell responses in the context of a sustained viral infection and determine if and how these responses contribute to the development of pathology and viral control in intestinal compartments. To accomplish this goal, we plan to (1) Evaluate the role of TRC in intestinal hyper-permeability and colitis during a sustained viral infection, (2) Investigate how IFN-I regulates intestinal TRC during sustained vs. acute viral infection, and (3) Identify the source(s) of IFN-I that regulate intestinal TRC during sustained vs. acute viral infection. Overall, our studies will use a combination of classic immunological techniques and cutting-edge technologies to characterize how TRC develop and are maintained during a long-term infection, as well as define the potential consequences of this response on tissue homeostasis and viral control. This work will significantly improve our understanding of tissue-specific T cell responses and their roles in protection and pathogenesis and open the door to directed therapeutics aimed at leveraging or tempering the power of tissue- resident responses to improve human health. Project Number: 1R01AI187302-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Elina Zuniga (+1 co-PI) | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $3,194,992 | Activity Code: R01 | Study Section: Viral Pathogenesis and Immunity Study Section [VPI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18730201