*Purpose: Currently, no immunotherapies have been clinically proven to prevent or treat chronic rejection. IL-15 is known to support memory T cell homeostasis. However, it is unknown whether IL-15 signaling is present in kidney allografts and if it maintains alloreactive tissue resident memory T (T_RM) cells that drive chronic rejection. We therefore targeted IL-15 signaling to determine whether (A) it was important for the maintenance of T_RM cells in the kidney allograft and (B) targeting this pathway could provide a treatment strategy for chronic rejection.

*Methods: Allogeneic (B6 x Balb/c) F1.Act-mOVA kidneys were transplanted into B6 recipients followed by adoptive transfer of OVA-specific T cell receptor-transgenic OT-I effector CD8 T cells 2 days post-transplantation. In this model, F1.OVA kidney grafts express OVA, which contains the SIINFEKL peptide recognized by OT-I cells in the context of H2-Kb. To test the role of IL-15 sensing by CD122, WT or CD122^fl/flR26^CreERT2+ OT-I cells were co-transferred into B6 recipients carrying F1.OVA grafts. To test the role of IL-15 presentation by CD215, F1.OVA grafts were transplanted into either CD215^fl/flR26^CreERT2- or CD215^fl/flR26^CreERT2+ recipients. For both experiments, tamoxifen was administered 4-8 weeks post-transplant, followed by harvest at 8 weeks. Anti-CD122 blocking antibody was administered either 4-6 weeks or continuously after 4 weeks post-transplant.

*Results: CD122 was upregulated and maintained on intragraft T cells 1 week and 8 weeks post-transplant. Deletion of CD122 on OT-I cells during maintenance significantly reduced their number (WT=94K, CD122^fl/fl=23K, p=0.0003). Deletion of CD215 in recipients resulted in significantly reduced number of OT-I and recipient polyclonal CD8 T cells (Fig. 1A, B). Similarly, short-term administration of anti-CD122 antibody resulted in significantly reduced number of intragraft T cells (Fig. 2A, B). Long-term administration of anti-CD122 preserved graft function as assessed by recipient survival (isotype MST=14wk, anti-CD122 MST>24wk, p=0.01).

*Conclusions: IL-15 signaling takes place in the renal allograft and contributes to the maintenance of T_RM cells. Disrupting IL-15 signaling through the use of anti-CD122 blocking antibody could serve as a potential approach to the prevention of chronic rejection.

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