| First Author | Mathews DV | Year | 2018 |
| Journal | J Clin Invest | Volume | 128 |
| Issue | 10 | Pages | 4557-4572 |
| PubMed ID | 30222140 | Mgi Jnum | J:266333 |
| Mgi Id | MGI:6202798 | Doi | 10.1172/JCI95914 |
| Citation | Mathews DV, et al. (2018) CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection. J Clin Invest 128(10):4557-4572 |
| abstractText | Interrupting T cell costimulatory signals as a strategy to control undesired immune responses, such as occur in autoimmunity or transplantation, has the potential to alleviate many of the unwanted side effects associated with current immunosuppressive therapies. Belatacept, a high-affinity version of CTLA4-Ig that blocks ligand ligation to CD28, has been approved for use in kidney transplant recipients. Despite the long-term benefits associated with its use, such as improved renal function and lower cardiovascular risk, a subset of patients treated with belatacept experience elevated rates of acute T cell-mediated rejection, tempering enthusiasm for its use. Here we demonstrate that costimulation-independent T cell alloreactivity relies on signaling through CD122, the shared IL-2 and IL-15 receptor beta-chain. Combined costimulatory and CD122 blockade improved survival of transplanted tissue in mice and nonhuman primates by controlling proliferation and effector function of CD8+ T cells. The high-affinity IL-2 receptor was dispensable for memory CD8+ T cell responses, whereas signaling through CD122 as a component of the high-affinity IL-15 receptor was critical for costimulation-independent memory CD8+ T cell recall, distinguishing specific roles for IL-2 and IL-15 in T cell activation. These studies outline a novel approach for clinical optimization of costimulatory blockade strategies in transplantation by targeting CD122. |
