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.