Kidney transplantation causes an immune response to non-self antigens called allograft rejection. The response to a kidney allograft can be divided into three phases: recognition of the alloantigen, activation of antigen-specific lymphocytes, and the effector phase of graft rejection. Allogeneic major histocompatibility complex (MHC) class I and class II molecules elicit a vigorous T-cell response. The alloresponse comprises CD4+ T cells that recognize allogeneic MHC indirectly after processing the molecules into peptide fragments. The majority of alloreactive T cells directly recognize intact allogeneic MHC molecules expressed on foreign cells. The interaction between the TCR of a T cell and the MHC/peptide complex on an antigen-presenting cell (APC) determines the specificity of the immune response. Two distinct signals are required for T-cell activation: one signal through the TCR and a second costimulatory signal through accessory molecules.