PROJECT SUMMARY / ABSTRACT Achieving meaningful restoration of function after nerve defects are repaired is still a major unmet clinical challenge. Due to disadvantages of nerve autografting, nerve graft alternatives are being increasingly used and desired for defect repair. But clinically, these alternatives do not promote consistent regeneration and recovery. Furthermore, we still do not understand what factors are critical to promote consistent nerve regeneration across repaired nerve defects that yields meaningful recovery. To understand mechanisms that promote nerve regeneration across nerve graft alternatives and functional recovery, we have used the clinically-relevant nerve graft alternative, acellular nerve allografts (ANAs), as a model. Recently, we determined a critical role for the adaptive immune system during regeneration across ANAs. We found that nerve regeneration across short ANAs repairing nerve defects in wild-type (WT) mice was robust, while regeneration across ANAs in T and B cell deficient mice (RAG1KO) was impaired. The ANAs within RAG1KO mice contained reduced Type 2 cytokine (i.e. IL-4) levels compared to WT ANAs. IL-4 expression was regulated via CD4 T cells and eosinophils. And in IL-4KO mice, regeneration across ANAs was also impaired. Overall, we have evidence that T cells contribute to nerve regeneration across ANAs through regulation of IL-4 expression within ANAs. Therefore, in our aims we will (1) dissect which adaptive immune cells, including CD4 T cells, affect nerve regeneration across ANAs, (2) identify how IL-4 expression is regulated within ANAs, and (3) determine the targets of IL-4 that promote nerve regeneration across ANAs. In summary, our studies will reveal the cells of the adaptive immune system contributing to nerve regeneration and demonstrate how IL-4 signaling promotes regeneration across nerve graft alternatives.