The MAPK cascades are major targets of genomic alterations caused by nuclear calcium signaling blockade. of nuclear calcium signaling, cytosolic calcium activating nuclear factor of activated T cells translocation directed the genomic response toward enhanced expression of genes that negatively modulate T cell activation and are associated with a hyporesponsive state. Thus, nuclear calcium controls the T cell fate decision between a proliferative immune response and tolerance. Modulators of nuclear calciumCdriven transcription may be used to develop a new type of pro-tolerance immunosuppressive therapy. Introduction Upon activation from the environment, many cell types use calcium signals for intracellular processing of information and the induction of appropriate biological responses through activating specific gene expression programs (Berridge et al., 2000; Clapham, 2007). To generate diversity in transmission transduction using a single second messenger, cells exploit the spatial and temporal profiles of calcium transients (Rizzuto and Pozzan, 2006; Bading, 2013). This process is well documented in the nervous system, where the partitioning of calcium signaling events in subcellular compartments and microdomains enables neurons to build a repertoire of stimulus-specific responses. For example, the genomic events that specify the expression patterns of target genes MLLT3 in synaptically stimulated neurons are differentially controlled by nuclear versus cytoplasmic calcium signals (Hardingham et al., 1997; Chawla et al., 1998; Mauceri et al., 2011). In particular, calcium signals in the cell nucleus function as important regulators of plasticity-related gene expression in neurons and are needed for the long-term implementation of different neuroadaptations including memory formation, acquired neuroprotection, and the development of chronic pain (Limb?ck-Stokin et al., 2004; Papadia et al., 2005; Zhang et al., 2009; Bading, 2013; Simonetti et al., 2013; Weislogel et al., 2013). Calcium regulates many cellular functions by forming a complex with calmodulin (CaM), a ubiquitously expressed calcium-binding protein. Upon binding of calcium, CaM increases its Sulfo-NHS-SS-Biotin affinity for its target proteins, which include the cytoplasmic serine/threonine phosphatase calcineurin (CaN) and the nuclear calcium/CaM-dependent protein kinase IV (CaMKIV; Crabtree, 1999; Hook and Means, 2001; Hogan et al., 2003). The instructive role of calcium signals in mounting adaptive responses in other tissues such as the heart or the immune system is generally appreciated (Feske et al., 2001; Oh-hora and Rao, 2008; Higazi et al., 2009). In nonneuronal cells, however, the complexity of calcium transients and possible functional diversity of spatially unique signals is usually less well explored. In antigen-stimulated T lymphocytes, increases in intracellular calcium levels are critical for the immune response (Dolmetsch et al., 1998; Lewis, 2001; Feske, 2007). Both local signals in the immunological Sulfo-NHS-SS-Biotin synapse (Lioudyno et al., 2008; Quintana et al., 2011) and cytoplasmic calcium microdomains have gene transcriptionCregulating functions (Di Capite et al., 2009; Kar et al., 2011). In contrast, the role of nuclear calcium signaling is usually virtually unexplored in T Sulfo-NHS-SS-Biotin cells. In particular, it has not been considered that calcium signals in the cytosol and the nucleus may serve unique functions in T cells that could explain differences in the responses to antigen challenge. T cells can undergo two very different types of physiological responses: activation, leading to a productive immune response, or anergy, leading to tolerance. Anergy is usually characterized by functional unresponsiveness and is induced when T cell receptor (TCR) activation is not accompanied by a costimulatory event (Macin et al., 2004). The costimulatory signal entails phosphatidylinositol-3-kinase and PKC signaling cascades; it is initiated physiologically by the binding of CD80/CD86 receptor around the antigen-presenting cell to the CD28 receptor and Sulfo-NHS-SS-Biotin can be induced in vitro by the exposure of T cells Sulfo-NHS-SS-Biotin to either CD28 antibodies or chemical inducers of PKC such as PMA. At the genomic level, the decision between activation and anergy depends on whether nuclear factor of activated T cells (NFAT), upon its stimulus-induced translocation to the nucleus, forms a transcription factor complex with AP1 (Macin et al.,.