**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** PRESENT KNOWLEDGE ABOUT THE IMMUNE RESPONSES THAT PROTECT PIGS FROM INFLUENZA VIRUS INFECTIONS IS LARGELY BASED ON OUR UNDERSTANDING OF A GROUP OF IMMUNE CELLS CALLED CONVENTIONAL T CELLS WHICH HAVE BEEN WELL DESCRIBED FOR DECADES. HOWEVER, MUCH LESS IS KNOWN ABOUT THE ROLE OF MORE RECENTLY DISCOVERED POPULATIONS OF UNCONVENTIONAL T CELLS CALLED INNATE-LIKE T CELLS (ITC). THESE ITCS SPECIALIZE IN PRODUCING LARGE QUANTITIES OF IMMUNE SIGNALING MOLECULES IN BARRIER ORGANS LIKE THE LUNG, AND PROBABLY MAKE PIVOTAL CONTRIBUTIONS TO INFLUENZA IMMUNITY. ALTHOUGH ITCS PROBABLY MAKE UP A SUBSTANTIAL PORTION OF THE SWINE INFLUENZA RESPONSE, MOST OF HOW THEY CONTRIBUTE TO PIG IMMUNITY CAN ONLY BE SPECULATED ABOUT FROM MOUSE MODELS WHICH HAVE SIGNIFICANT DRAWBACKS, INCLUDING THAT MICE COMPLETELY LACK AN ENTIRE CATEGORY OF ITCS CALLED GROUP I CD1-RESTRICTED T-CELLS. WE HYPOTHESIZE THAT ITCS PLAY IMPORTANT ROLES IN EARLY IMMUNE RESPONSES DURING INFLUENZA INFECTIONS AS WELL AS IN SHAPING IMMUNE MEMORY AGAINST SUBSEQUENT INFECTIONS. WE WILL TEST THIS THEORY USING GENETICALLY MODIFIED SWINE INDIVIDUALLY LACKING THREE DIFFERENT TYPES OF ITCS. FIRSTLY, ITC-DEFICIENT AND -INTACT PIGS WILL BE COMPARED FOR THEIR SUSCEPTIBILITY TO DIFFERENT INFLUENZA A VIRUS STRAINS USING A RANGE OF INNOVATIVE TOOLS. SECONDLY, WE WILL DETERMINE THE RESISTANCE OF ITC-DEFICIENT AND INTACT PIGS TO SUBSEQUENT CHALLENGE WITH DISTANT AND CLOSELY RELATED INFLUENZA VIRUS STRAINS. THESE EXPERIMENTS WILL PROVIDE THE FIRST COMPREHENSIVE EXAMINATION OF ITCS TO THE HEALTH OF PIGS, WHICH HAS THE POTENTIAL TO TRANSFORM CURRENT UNDERSTANDING OF HOW SWINE PROTECT THEMSELVES AGAINST RESPIRATORY VIRUSES.