Organ transplantation is thus far the only cure for patients with a terminal organ failure. Understanding immunological mechanisms underlying graft tolerance vs. graft rejection is critical in clinical transplantation and improving quality of life in transplant patients. Significance and clinical relevance of this project reach over from basic Immunology to translational research and patient care in a tangible way. Therapies targeting adverse inflammation have succeeded in prolonging allograft survival and improving its function post-transplant (3, 4);however, the mechanisms by which inflammation modulates allograft response are not fully understood. The goal of the proposed project is to determine the role of interieukin (IL)-21 in the allograft response and the balance between graft-protective and graft-destructive immunity. IL- 21 is a T-cell growth factor associated with generation of inflammatory Thi 7 cells (8, 16). Although amplified expression of IL-21 accompanies allograft rejection (14), the data on its role in allograft response are sparse. Moreover, pathogenic role of IL-21/Th17 axis in organ transplantation remains to be determined (15, 19). We will test the hypothesis that IL-21 alters the balance between graft-destructive effector T-cells and graft- protective regulatory T-cells thus favoring donor-destructive immunity. In the specific aim 1, we will define the impact of IL-21 on the balance and detailed program of donor-activated, graft destructive effector T-cells and protective type regulatory CD4cells. Immunodeficient RAG mice, adoptively transferred with effector and regulatory T-cells in 1:1 ratio, will receive allogeneic skin transplant. IL-21 will be administered in vivo through continuously releasing osmotic pump while control animals will not receive any cytokine. Both antigen non-specific (DBA/2 to BL/6) and antigen-specific (bm12 to ABM) transplant models will be tested. The temporal analysis of allograft response will provide information on the lineage commitment of T-cells in vivo and outline their relative proportion at the different time-points post-transplant. In the specific aim 2, we will define the effect of IL-21 on allograft survival and graft transcriptional profile. Skin allograft gene expression will be analyzed at the time of implantation and serially thereafter in both untreated and IL-21 treated recipients. This study will investigate the hypothesis that IL-21 accelerates allograft rejection and fosters Thi7 effector response in the target organ.