Interleukin-21 (IL-21), a member of the type I cytokine family, regulates central functions of immunity. Within this family, signaling is mediated via a receptor complex consisting of a high-affinity receptor chain and the common gamma-chain (IL-2Rgamma, CD132). We analyze the mRNA expression of IL-21, IL-21 receptor-alpha (IL-21Ralpha) and family members IL-15, IL-2Rgamma, IL-21Ralpha, IL-15Ralpha, IL-2/15Rbeta, as well as IL-2Ralpha (CD25) in leukocytes isolated by vascular perfusion of rat renal allografts. Mononuclear leukocytes expressed increased amounts of IL-21Ralpha mRNA and protein during acute rejection. Most IL-21Ralpha-positive cells were monocytes. Furthermore, IL-21 and IL-2Ralpha mRNA expression was strongly increased. No changes in IL-2Rgamma, IL-2/15Rbeta, IL-15, and IL-15Ralpha mRNA expression levels were seen. In conclusion, we demonstrate that IL-21Ralpha expression is induced in intravascular monocytes in vivo in response to allogeneic transplantation. The function of the IL-21/IL-21R system in monocytes and during acute allograft rejection remains to be established.