Research in mice and non-human primates has demonstrated that costimulation-blockade resistant organ rejection following transplantation is primarily mediated by donor-reactive CD8+ T cells. Controlling these alloreactive T cell responses is imperative for improving long-term outcomes in pediatric and adult transplant recipients. The Ig-superfamily member 2B4 (SLAMf4, CD244) has been shown to be inducibly expressed on -CD8+ T cells. Our recent studies suggest that 2B4 plays a functional role in the inhibition of donor-reactive CD8+ T cell responses following CD28 costimulation blockade in vivo, raising the possibility that 2B4 itself could be a therapeutic target to attenuate allograft rejection. Preliminary data suggest that 2B4 may function as a costimulator during primary pathogen- specific CD8+ T cell activation and raise the exciting possibility that 2B4 could be specifically manipulated to attenuate acute graft rejection mediated by alloreactive CD8+ T cells following transplantation, while simultaneously maintaining functional immune responses capable of defending the host from pathogen infections. This work will test the concept that graft-specific and pathogen-specific CD8+ T cells express different complements of costimulatory and coinhibitory molecules. We propose that certain signaling pathways in T cells may be differentially engaged in the setting of infection and transplant and that these responses can be exploited to maximize protective immunity and minimize the risk of rejection following transplantation.