Glutamate Receptor Interacting Protein 1 Regulates CD4 + CTLA‐4 Expression and Transplant Rejection

PDZ domains are common 80‐ to 90‐amino‐acid regions named after the first three proteins discovered to share these domains: postsynaptic density 95, discs large, and zonula occludens. PDZ domain‐containing proteins typically interact with the C‐terminus of membrane receptors. Glutamate receptor interacting protein 1 ( GRIP 1), a seven– PDZ domain protein scaffold, regulates glutamate receptor surface expression and trafficking in neurons. We have found that human and mouse T cells also express GRIP 1. T cell–specific GRIP 1 −/− mice >11 weeks old had prolonged cardiac allograft survival. Compared with wild‐type T cells, in vitro stimulated GRIP 1 −/− T cells had decreased expression of activation markers and increased apoptotic surface marker expression. Surface expression of the strong T cell inhibitory molecule cytotoxic T lymphocyte antigen‐4 ( CTLA ‐4) was increased on GRIP 1 −/− T cells from mice >11 weeks old. CTLA ‐4 increases with T cell stimulation and its surface expression on GRIP 1 −/− T cells remained high after stimulation was removed, indicating a possible internalization defect in GRIP 1‐deficient T cells. CTLA ‐4–blocking antibody treatment following heart transplantation led to complete rejection in T cell GRIP 1 −/− mice, indicating that increased CTLA ‐4 surface expression contributed to the extended graft survival. Our data indicate that GRIP 1 regulates T cell activation by regulating CTLA ‐4 surface expression.