The regulatory role of naturally occurring CTLA-4 splice variants:the suppressive function of short splice variant 1/4 WT CTLA-4 (B91)

Abstract

Abstract Cytotoxic T lymphocyte Antigen 4 (CTLA-4) is an important cell surface molecule that inhibits T cell activation. Four splice variants of CTLA-4 have been identified, indicating the regulatory complexity of CTLA-4. In this study, we characterized the biology of the shortest splice variant 1/4WT CTLA-4 and its functional correlation to full length (FL CTLA-4). 1/4WT CTLA-4 mRNA was found in quiescent CD4+ T cells and upregulated after immunization with MOG35-55 peptide. The kinetic expression of 1/4WT was opposite to FL CTLA-4. To test functions of 1/4WT CTLA-4, we transduced CD4 T cells with a retroviral vector coexpressing 1/4WT CTLA-4 and the green fluorescent protein (GFP). FL CTLA-4 was downregulated on the cell surface by 1/4WT overexpression, which consequently enhanced antigen specific T cell responses by enhancing T cell proliferation and cytokine production in vitro. This functional correlation between 1/4WT and FL CTLA-4 had profound influence on effector CD4 T cell function. Mice adoptively transferred with MOG35-55 specific CD4 T cells containing ectopically expressed 1/4WT CTLA-4 showed dramatically exacerbated EAE disease, increased CD4 T cell proliferation, and increased IFN gamma and IL-17 production. These data suggest that 1/4WT CTLA-4 plays an important role in regulating T cell activation by affecting expression and/or function of FL CTLA-4.