Project Summary/ Abstract Traumatic brain injury (TBI), and the ensuing post-traumatic behavioral and neurological syndromes, are serious clinical problems. Approximately 5 million people in the U.S. are living with the chronic consequences of TBI, and optimal treatment strategies are lacking. We have discovered that specific components of the immune system contribute to neuropathology after a TBI. More specifically, we have discovered that CD74, a protein that functions via unique mechanisms that distinctly contribute to either the innate or the adaptive immune response, can be manipulated to improve neurodegeneration and behavioral outcomes after TBI. Our proposal is based on three primary observations: 1) Our preliminary data implicating full-length CD74 signaling via macrophage migration inhibitory factor (MIF)-binding in the astrocytic response to TBI; 2) Our data indicating that depleting full-length CD74 or antagonizing the proteolytic cleavage product(s) of CD74, class II invariant peptide (CLIP), are anti- inflammatory and neuroprotective after TBI; 3) Recent evidence from human clinical TBI patients and experimental TBI in animal models, showing strong evidence for an adaptive immune response, potentially including autoimmunity. Taken together, these studies are important because: A) they will assess the distinct contributions of CD74 to the innate and adaptive immune responses following TBI; B) they will distinguish between the unique mechanisms of CD74 that contribute to TBI-induced neuropathology and post-traumatic behavioral syndromes; and C) they will determine if targeting specific components of CD74 might be a potential therapeutic strategy following TBI.