Project Grant R01AI186330

T CELL MEMORY TO VIRUSES - CHRONIC VIRAL INFECTIONS ARE CHARACTERIZED BY A STATE OF T CELL DYSFUNCTION THAT IS ASSOCIATED WITH EXPRESSION OF THE PD-1 (PROGRAMMED CELL DEATH 1) INHIBITORY RECEPTOR. A BETTER UNDERSTANDING OF THE MECHANISMS THAT REGULATE CD8 T CELL RESPONSES DURING CHRONIC VIRAL INFECTION IS REQUIRED TO IMPROVE IMMUNOTHERAPIES THAT WILL INCREASE T CELL FUNCTION AND REDUCE VIRAL LOAD. WE HAVE RECENTLY IDENTIFIED A NOVEL POPULATION OF PD-1+ TCF-1+ VIRUS SPECIFIC CD8 T CELLS THAT ACT AS STEM CELLS TO MAINTAIN T CELL RESPONSES DURING CHRONIC INFECTION OF MICE WITH LYMPHOCYTIC CHORIOMENINGITIS VIRUS (LCMV). THE STUDIES PROPOSED IN THE APPLICATION ARE FOCUSED ON UNDERSTANDING HOW THESE VIRUS SPECIFIC STEM-LIKE CD8 T CELLS ARE GENERATED AND MAINTAINED DURING CHRONIC INFECTION AND HOW THIS INFORMATION CAN BE USED TO DEVELOP RATIONAL APPROACHES FOR OPTIMIZING PD-1 DIRECTED IMMUNOTHERAPY. IN PARTICULAR, WE ASK THE FOLLOWING QUESTIONS: 1) HOW DO THESE CELLS MAINTAIN THEIR QUIESCENCE AND THE STEM-LIKE STATE WHILE LIVING IN A SEA OF ANTIGEN AND GETTING TCR SIGNALS? 2) ARE THERE ANY NOVEL INHIBITORY PATHWAYS THAT ARE SELECTIVELY EXPRESSED BY THE STEM-LIKE CD8 T CELLS TO MAINTAIN THEIR LIFESTYLE DURING CHRONIC INFECTION? 3) HOW CAN WE INCREASE THE NUMBER OF THESE CRUCIAL STEM-LIKE CD8 T CELLS? 4) WHAT ARE THE MOST OPTIMAL PD-1 COMBINATION THERAPIES FOR HARNESSING THE FULL POTENTIAL OF THE STEM-LIKE CD8 T CELLS? THE FOLLOWING SPECIFIC AIMS ARE PROPOSED TO ADDRESS THESE QUESTIONS: SPECIFIC AIM 1: DETERMINE THE ROLE OF INHIBITORY MOLECULES SELECTIVELY EXPRESSED BY VIRUS-SPECIFIC STEM-LIKE CD8 T CELLS IN REGULATING THEIR QUIESCENCE AND EFFECTOR CELL OUTPUT. SPECIFIC AIM 2: HARNESSING THE POTENTIAL OF PD-1+ STEM-LIKE CD8 T CELLS FOR OPTIMAL IMMUNOTHERAPY IN CHRONIC VIRAL INFECTION.