IMMUNOLOGY Regulation of T Cell Activation by Calcineurin Inhibition

T cell receptor activation mobilizes intracellular calcium and thereby stimulates the calcium-dependent phosphatase calcineurin, which dephosphorylates NF-AT (nuclear factor of activated T cells) transcription factors and leads to their translocation to the cell nucleus and transcriptional activation of target genes. Although antigen-specific clonal expansion of T cells depends on calcineurin-dependent expression of cytokines and cytokine receptors, restimulation leads to the death of T helper type 1 (T_H1) cells through the calcineurin-dependent expression of Fas ligand. It is not clear why primary stimulation does not promote Fas ligand expression (and cell death). Ryeom et al. investigated the effects of the calcipressins (Csps) on calcineurin activity and T cell responses, to determine whether these calcineurin inhibitors could determine whether calcineurin stimulation leads to T cell proliferation or T cell death. Csps suppressed calcineurin dephosphorylation in vitro and associated with activated calcineurin in vivo. When coexpressed in BHK cells, Csp1 prevented calcium-dependent translocation of NF-ATc3 to the nucleus. The T cells of Csp1-deficient mice showed elevated calcineurin activity and decreased cell proliferation and production of interferon- (IFN-, a T_H1-specific cytokine) after activation. Moreover, Csp1-deficient Th1 cells expressed Fas ligand during primary stimulation and underwent premature cell death. Csp-1-deficient cell proliferation, IFN- production, and viability were rescued by treatment with low doses of a calcineurin inhibitor, and Fas ligand expression was reduced. The authors used graded stimulation of the T cell receptor to differentially activate calcineurin and observed a pattern of high- and low-threshold gene expression in wild-type cells. In Csp1-deficient T cells, gene transactivation occurred at lower stimulus thresholds. Thus, genes such as Fas ligand, which require high levels of stimulation, appear to be repressed during primary stimulation through Csp-dependent modulation of calcineurin activity.

S. Ryeom, R. J. Greenwald, A. H. Sharpe, F. McKeon, The threshold pattern of calcineurin-dependent gene expression is altered by loss of the endogenous inhibitor calcineurin. Nat. Immunol. 4, 874-881 (2003). [Online Journal]