Project Grant F31AI203423

INVESTIGATING THE EFFECT OF VARIABLE INTERFERON SIGNALING ON CD4+ T CELLS - PROJECT SUMMARY INFLAMMATION UNDERLIES ALL IMMUNE RESPONSES, BUT IT IS A DOUBLE-EDGED SWORD: TOO LITTLE IMPAIRS DANGER SENSING, LYMPHOCYTE FUNCTION, AND MEMORY FORMATION, WHILE TOO MUCH DRIVES CYTOTOXICITY AND IMMUNOPATHOLOGY. UNDERSTANDING ITS CONSEQUENCES IS ESSENTIAL FOR OPTIMIZING IMMUNITY DURING INFECTION, VACCINATION, AND AGING. MY PROJECT EXAMINES HOW PRIMING IN AN INFLAMED ENVIRONMENT SHAPES LYMPHOCYTE DIFFERENTIATION, FOCUSING ON THE EFFECT OF TYPE I INTERFERON (IFN-I) ON CD4 MEMORY T CELLS. IFN-I IS BROADLY INDUCED DURING VIRAL INFECTION AND IS KNOWN TO DURABLY IMPRINT INTERFERON-RELATED PROGRAMS IN MEMORY B CELLS, YET ITS INFLUENCE ON CD4 T CELL MEMORY DIFFERENTIATION IS UNCLEAR. DEFINING HOW ELEVATED INFLAMMATION AFFECTS CD4 T CELL DIFFERENTIATION AND ANTIBODY PRODUCTION MAY REVEAL AVENUES TO IMPROVE VACCINE EFFICACY. OUR LAB HAS SHOWN THAT MEMORY CD4 T CELLS RETAIN DISTINCT TRANSCRIPTIONAL SIGNATURES DEPENDING ON WHETHER THEIR INITIAL EXPOSURE WAS TO SARS-COV-2 VACCINATION OR INFECTION, WITH INFLAMMATION-PRIMED CELLS ENRICHED FOR IFN-I-RELATED GENES. BECAUSE IFN-I AND BROADER INFLAMMATORY SIGNALS ARE STRONGER DURING INFECTION THAN VACCINATION, WE ASK WHETHER THE MAGNITUDE OF IFN-I SIGNALING INFLUENCES CD4 T CELL MEMORY DIFFERENTIATION. I HYPOTHESIZE THAT IFN-I MODIFIES CD4 T MEMORY DIFFERENTIATION AND FUNCTION UPON SECONDARY INFECTION. I WILL TEST THIS HYPOTHESIS USING A NOVEL MOUSE SYSTEM WITH VARIABLE IFN-I SIGNALING THAT INCLUDES BOTH AN ESTABLISHED MUTANT WITH ENHANCED IFN-I ACTIVITY AND A NEW MOUSE LINE I GENERATED WITH ATTENUATED SIGNALING. BY IMMUNIZING AND INFECTING THESE MICE, I WILL ASSESS HOW TUNABLE IFN-I RESPONSES SHAPE CD4 T CELL MEMORY DIFFERENTIATION AND FUNCTION DURING PRIMARY AND SECONDARY IMMUNE RESPONSES. THIS WORK USES A UNIQUE MODEL SYSTEM TO DEFINE HOW IFN-I SIGNALING PROGRAMS CD4 MEMORY T CELLS AND INFLUENCES THEIR RECALL RESPONSES, PROVIDING INSIGHTS THAT ARE ESSENTIAL FOR UNDERSTANDING ADAPTIVE IMMUNITY AND FOR GUIDING THE DEVELOPMENT OF EFFECTIVE LONG LASTING VACCINES.