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Glutamate Receptor Interacting Protein 1 Regulates CD4 + CTLA‐4 Expression and Transplant Rejection
Author(s) -
Modjeski K. L.,
Levy S. C.,
Ture S. K.,
Field D. J.,
Shi G.,
Ko K.,
Zhu Q.,
Morrell C. N.
Publication year - 2016
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.13623
Subject(s) - pdz domain , cytotoxic t cell , receptor , microbiology and biotechnology , t cell , glutamate receptor , transplantation , biology , medicine , immunology , immune system , in vitro , biochemistry
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.