*Purpose: We have previously demonstrated that donor kidney-intrinsic innate immunity determines the severity of delayed graft function (DGF) in kidney transplantation and potentiates long kidney allograft survival. This study aimed to further delineate cellular and molecular mechanisms underlying donor kidney derived immunoregulation in a mouse model of DGF.

*Methods: Kidneys from C57BL/6 (B6) or BALB/c mice were harvested and stored in cold UW solution for 3 hours, and then transplanted into full MHC-mismatched binephrectomized C3H mice (B6 allografts vs BALB/s allografts), respectively. Graft functions were evaluated at post-transplant day (POD) 1, 7 and 14 by renal function panels. Histology, RNA sequencing (RNA-seq) and immunophenotyping were performed at the endpoints (POD2 or POD14).

*Results: We observed that transplant of kidneys from BALB/c mice with prolonged cold ischemia time had significantly reduced tissue inflammation and improved renal function, compared to kidney allografts from B6 mice, not only in the initial ischemia and reperfusion (I/R) phase (POD1-2) of transplantation but also in acute rejection phase (POD7-14). Interestingly, Immunophenotypic analysis at POD14 showed that compared with B6 kidney allografts, BALB/c kidney allografts exhibited significantly higher percentage and more absolute cell number of Tregs both in spleen and grafts than those received B6 grafts, which coincided with increased frequencies of myeloid cells that expressed higher levels of MHCII, MerTK and CD273 (PD-L2). RNA-seq was performed on the grafts at POD2 to determine the signaling pathways that may contribute to increased Tregs. The results revealed that expression of genes, including cytokines/chemokines (IL-10Ra, GzmB, Icos, CXCR4) and transcription factors (satb1, ETS1, batf and Foxo3) that are associated with Treg differentiation/function/survival was significantly enriched in the BALB/c allografts, as opposed to B6 allografts.

*Conclusions: Donor genetic background dictates expression of genetic signatures that regulates differentiation and accumulation of regulatory T cells in the kidney allografts. These findings underscore the importance of immunomodulating donor organs in improving transplant outcome.

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