AUTOIMMUNE DISEASE Ligand Binding Not Required for Inhibition

A splice variant of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) that lacked the ligand-binding domain (liCTLA-4) was recently implicated by genetic analysis in a mouse model of type 1 diabetes. CTLA-4 isoforms are negative regulators of T cell signaling, and loss of their activity is implicated in various autoimmune diseases. Vijayakrishnan et al. showed that, in mice, liCTLA-4 mRNA and protein were present in spleen cell lysates. In addition, the protein was partially localized to the plasma membrane when expressed in transfected HEK 293 cells. The amount of liCTLA-4 in T cells changes with activation, such that liCTLA-4 is highly abundant in inactivated cells, decreases shortly after activation, and then returns to an abundant state. When liCTLA-4 is decreasing, the amount of full-length CTLA-4 (flCTLA-4) is increasing. Both flCTLA-4 and liCTLA-4 (expressed by retroviral infection) inhibited proliferative responses and cytokine production of T cells from mice deficient in CTLA-4, B7.1, and B7.2 (B7 proteins are costimulatory ligands for flCTLA-4). In CD3⁺ T cells from wild-type mice, flCTLA-4 and liCTLA-4 coimmunoprecipitated together and associated with the T cell receptor subunit (TCR) and the phosphatase SHP-2. However, liCTLA-4 alone did not associate with SHP-2. When CD3 is cross-linked, the presence of either flCTLA-4 or liCTLA-4 diminished (flCTLA-4) or abolished (liCTLA-4) TCR phosphorylation. Emphasizing the potential importance of liCTLA-4 in vivo, the authors found that mice susceptible to autoimmune disease exhibited lower mRNA levels for liCTLA-4 in memory or regulatory T cells than that observed in cells from mice resistant to autoimmune disease.

L. Vijayakrishnan, J. M. Slavik, Z. Illés, R. J. Greenwald, D. Rainbow, B. Greve, L. B. Peterson, D. A. Hafler, G. J. Freeman, A. H. Sharpe, L. S. Wicer, V. K. Kuchroo, An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity 20, 563-575 (2004). [Online Journal]