Deficiency Of N-Myristoylation Reveals Calcineurin Activity As Regulator Of Ifn-Gamma- Producing Gamma Delta T Cells

gamma delta T cell subsets can be characterized, in part, by their secretion of select proinflammatory cytokines. The molecular mechanisms driving the diverse fates of gamma delta T cells have not been elucidated. We have previously shown that the attachment of myristic acid to the N-terminal glycine of proteins, termed N-myristoylation, is essential for alpha beta T cell development and activation. Here, we explore the potential role of this lipid modification on the activation of gamma delta T cells. In the absence of N-myristoylation, the CD27(+) gamma delta T cell subset was dominantly affected. The cells produced high levels of IFN-gamma upon stimulation. In addition, they were more sensitive to inhibition of the CaN-Nfat pathway than were gamma delta T cells with myristoylated CaN. N-Myristoylation was found to modulate activity of phosphatase CaN, a regulator of Nfat. In summary, the CaN-Nfat pathway regulates development and function of IFN-gamma-producing gamma delta T cells, and its balanced activity is strongly dependent on CaN N-myristoylation.