Project Grant F31AI197568

IL-10 AND PD-1 COOPERATE TO LIMIT TERMINAL DIFFERENTIATION OF CD8 T CELLS IN CHRONIC VIRAL INFECTION - PROJECT SUMMARY IMMUNOTHERAPIES SUCH AS IMMUNE CHECKPOINT BLOCKADES AND ADOPTIVE CELL TRANSFER THERAPY HAVE PROVEN REVOLUTIONARY FOR THE TREATMENT OF CANCER AND SOME CHRONIC VIRAL INFECTIONS, INCLUDING HIV AND CERTAIN MELANOMAS. HOWEVER, THESE STRATEGIES FOCUS ON THE REINVIGORATION OF CD8 T CELLS THAT HAVE ENTERED A DYSFUNCTIONAL STATE, KNOWN AS T CELL EXHAUSTION, AND CAN BE LACKLUSTER. RECENT STUDIES HAVE FOUND A HETEROGENEITY OF CELL POPULATIONS EXIST IN CD8 T CELL EXHAUSTION, WITH A SELF-RENEWING AND QUIESCENT PROGENITOR CD8 T CELL THAT CAN GIVE RISE TO BOTH CYTOTOXIC EFFECTOR CELLS, AS WELL AS TERMINALLY EXHAUSTED CELLS. THE PROGENITOR CD8 T CELL POPULATION CAN REINVIGORATE THE CD8 T CELL RESPONSE UPON TREATMENT WITH PD-1 IMMUNE CHECKPOINT BLOCKADE, AS OBSERVED IN BOTH CHRONIC VIRAL INFECTION AND IN SOME SOLID TUMORS. HOWEVER, THE MECHANISM BY WHICH PROGENITOR CD8 T CELLS REMAIN UNDIFFERENTIATED IN INFLAMMATORY ENVIRONMENTS OF CANCER AND CHRONIC INFECTION REMAIN ELUSIVE. THEREFORE, THE OVERARCHING GOAL OF THIS FELLOWSHIP APPLICATION IS TO INVESTIGATE POTENTIAL IMMUNOSUPPRESSIVE SIGNALS THAT MAY LIMIT THE TERMINAL DIFFERENTIATION OF PROGENITOR CD8 T CELLS, SPECIFICALLY IL-10 AND PD-1. IT IS HYPOTHESIZED THAT IMMUNOSUPPRESSIVE FACTORS, INCLUDING IL-10 AND PD-L1 ARE LOCATED WITHIN THE NICHE BY WHICH THE PROGENITOR CD8 T CELLS LOCALIZE TO WITHIN THE MURINE SPLEEN. THUS, AIM 1 WILL DETERMINE THE CELLULAR NETWORK AND EXTRINSIC IMMUNOSUPPRESSIVE FACTORS SURROUNDING THE PROGENITOR POPULATION WITHIN THE MURINE SPLEEN IN THE LCMV CLONE 13 CHRONIC INFECTION MODEL. IT IS HYPOTHESIZED THAT IL-10 AND PD-L1 WILL BE HIGHLY EXPRESSED WITHIN THE WHITE PULP, WHEREBY THE PROGENITOR CD8 T CELLS HAVE BEEN SHOWN TO COMMONLY LOCALIZE, COMPARED TO THE RED PULP. ADDITIONALLY, AIM 2 WILL DETERMINE THE MANNER BY WHICH IL-10 AND PD-L1 MODULATE THE CD8 T CELL DIFFERENTIATION TRAJECTORY TO LIMIT TERMINAL DIFFERENTIATION IN CHRONIC VIRAL INFECTION. THIS STUDY WILL BE CONDUCTED AT NORTHWESTERN UNIVERSITY'S FEINBERG SCHOOL OF MEDICINE. THROUGH THE INTERACTIONS OF THIS RESEARCH WITH IMMUNOLOGISTS, CANCER BIOLOGISTS, AND OTHER FACULTY AND STAFF, MULTIDISCIPLINARY MENTORSHIP WILL OCCUR. THE MENTORSHIP GAINED FROM THIS RESEARCH WILL LEAD TO OBTAINING EXCELLENT TRAINING IN THE FORMS OF RIGOROUS RESEARCH TRAINING, COMPUTATIONAL BIOINFORMATICS TRAINING, FOCUSED MANUSCRIPT FORMULATION, AND ALLOW FOR PRESENTATIONS AT BOTH REGIONAL AND NATIONAL SCIENTIFIC MEETINGS. THIS PROJECT WILL LEAD TO A BETTER UNDERSTANDING OF THE MAINTENANCE REQUIREMENTS OF THIS STEM-LIKE PROGENITOR POPULATION, LEADING TO THE POTENTIAL DEVELOPMENT OF NOVEL IMMUNOTHERAPIES DESIGNED TO REINVIGORATE THE CD8 T CELL RESPONSE TO CHRONIC VIRAL INFECTION AND SOME CANCERS.