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Calcineurin links calcium signaling to transcriptional responses in the immune, nervous and cardiovascular systems. To determine the function of the calcipressins, a family of putative calcineurin inhibitors, we assessed the calcineurin-dependent process of T cell activation in mice engineered to lack the gene encoding calcipressin 1 (Csp1). Csp1 regulated calcineurin in vivo, and genes triggered in an immune response had unique transactivation thresholds for T cell receptor stimulation. In the absence of Csp1, the apparent transactivation thresholds for all these genes were shifted because of enhanced calcineurin activity. This unbridled calcineurin activity drove Fas ligand expression, which normally requires high T cell receptor stimulation and results in the premature death of T helper type 1 cells. Thus, calcipressins modulate the pattern of calcineurin-dependent transcription, and may influence calcineurin activity beyond calcium to integrate a broad array of signals into the cellular response. [ABSTRACT FROM AUTHOR]

The article focuses on the research on dendritic cells (DCs) showing that tolerance induced by resting DCs is dependent on engagement of the T cell inhibitory receptors PD-1 and CTLA-4. DCs are the principal cell type that display peptide antigens for the initiation of adaptive immune responses involving T cells and are also capable of shutting lymphocytes off, thus inducing tolerance in T cells. It remains unclear why resting DCs might preferentially engage inhibitory receptors of T cells. One hypothesis is that this phenomenon is related to the expression of costimulatory ligands and the affinities of activating versus inhibitory receptors for these ligands. A different but not mutually exclusive mechanism is that inhibition simply reflects a change in the activation threshold of T cells.