RIP2 Is Required for NOD Signaling But Not for Th1 Cell Differentiation and Cellular Allograft Rejection

Two previous reports that receptor-interacting protein (RIP)-2 knockout (RIP2^–/–) mice had defective nuclear factor-kappa B (NF-κB) signaling and T helper (Th)1 immune responses had led us to believe that this putative serine-threonine kinase might be a possible target for transplant immunosuppression. Thus, we tested whether RIP2^–/– mice were able to reject vascularized allografts. Surprisingly, we found that T cells from RIP2^–/– mice proliferated and produced interferon (IFN)-γ after allostimulation in vitro. Moreover, naïve RIP2^–/– CD4⁺ T cells differentiated normally into Th1 or Th2 cells under appropriate cytokine microenvironments. Consistent with these findings, no difference in allograft survival was observed between wild-type and RIP2^–/– recipient mice, and rejection had similar pathology and cytokine profiles in both types of recipients. RIP2 deficiency was associated with defective NOD signaling, but this did not affect T-cell receptor (TCR)-dependent activation of the canonical NF-κB signaling or expression of NF-κB genes in rejecting allografts. Our data demonstrate that RIP2-deficient mice have intact canonical NF-κB signaling and can mount Th1-mediated alloresponses and reject vascularized allografts as efficiently as wild-type mice, thus arguing against RIP2 as a primary target for immunosuppression.