Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabin1 results in enhanced cytokine gene expression in T cells

Cabin1 binds calcineurin and myocyte enhancer factor 2 (MEF2) through its C OOH-terminal region. In cell lines, these interactions were shown to inhibi t calcineurin activity after T cell receptor (TCR) signaling and transcript ional activation of Nur77 by MEF2. The role of these interactions under phy siological conditions was investigated using a mutant mouse strain that exp resses a truncated Cabin1 lacking the COOH-terminal calcineurin and MEF2 bi nding domains. T and B cell development and thymocyte apoptosis were normal in mutant mice. In response to anti-CD3 stimulation, however, mutant T cel ls expressed significantly higher levels of interleukin (IL)-2, IL-4, IL-9, IL-13, and interferon gamma than wild-type T cells. The enhanced cytokine gene expression was not associated with change in nuclear factor of activat ed T cells (NF-AT)c or NF-ATp nuclear translocation but was preceded by the induction of a phosphorylated form of MEF2D in mutant T cells. Consistent with the enhanced cytokine expression, mutant mice had elevated levels of s erum immunoglobulin (Ig)G1, IgG2b, and IgE and produced more IgG1 in respon se to a T cell-dependent antigen. These findings suggest that the calcineur in and MEF2 binding domain of Cabin1 is dispensable for thymocyte developme nt and apoptosis, but is required for proper regulation of T cell cytokine expression probably through modulation of MEF2 activity.