In lymphocytes, the three NFAT factors NFATc1 (also designated as NFAT2), NFATc2 (NFAT1), and NFATc3 (NFAT4 or NFATx) are expressed and are the targets of immune receptor signals, which lead to a rapid rise of intracellular Ca++, the activation of phosphatase calcineurin, and to the activation of cytosolic NFATc proteins. In addition to rapid activation of NFAT factors, immune receptor signals lead to accumulation of the short NFATc1/αA isoform in lymphocytes which controls their proliferation and survival. In this mini-review, we summarize our current knowledge on the structure and transcription of the Nfatc1 gene in lymphocytes, which is controlled by two promoters, two poly A addition sites and a remote downstream enhancer. The Nfatc1 gene resembles numerous primary response genes (PRGs) induced by LPS in macrophages. Similar to the PRG promoters, the Nfatc1 promoter region is organized in CpG islands, forms DNase I hypersensitive sites, and is marked by histone tail modifications before induction. By studying gene induction in lymphocytes in detail, it will be important to elucidate whether the properties of the Nfatc1 induction are not only typical for the Nfatc1 gene but also for other transcription factor genes expressed in lymphocytes.

The link between the extensive usage of calcineurin (CN) inhibitors cyclosporin A and tacrolimus (FK506) in transplantation medicine and the increasing rate of opportunistic infections within this segment of patients is alarming. Currently, how peritoneal infections are favored by these drugs, which impair the activity of several signaling pathways including the Ca ++ /CN/NFAT, Ca ++ /CN/cofilin, Ca ++ /CN/BAD, and NF-κB networks, is unknown. Here, we show that Saccharomyces cerevisiae infection of peritoneal resident macrophages triggers the transient nuclear translocation of NFATc1β isoforms, resulting in a coordinated, CN-dependent induction of the Ccl2, Ccl7, and Ccl12 genes, all encoding CCR2 agonists. CN inhibitors block the CCR2-dependent recruitment of inflammatory monocytes (IM) to the peritoneal cavities of S. cerevisiae infected mice. In myeloid cells, NFATc1/β proteins represent the most prominent NFATc1 isoforms. NFATc1/β ablation leads to a decrease of CCR2 chemokines, impaired mobilization of IMs, and delayed clearance of infection. We show that, upon binding to a composite NFAT/BCL6 regulatory element within the Ccl2 promoter, NFATc1/β proteins release the BCL6-dependent repression of Ccl2 gene in macrophages. These findings suggest a novel CN-dependent cross-talk between NFAT and BCL6 transcription factors, which may affect the outcome of opportunistic fungal infections in immunocompromised patients.Keywords: BCL6 r CCL2 r CCR2 r Inflammatory monocytes r NFATc1 r Opportunistic infection Additional supporting information may be found in the online version of this article at the publisher's web-site [4,5]. Although ablation of CN-B compromises neutrophil-dependent killing of fungal pathogens ex vivo [6], it is still not completely clear how CsA and FK506 facilitate fungal and other opportunistic infections. We will show here that in peritoneal macrophages CsA and FK506 inhibit the synthesis of chemokines that attract neutrophils and inflammatory monocytes (IMs) to the site of infection.Tissue-specific resident macrophages [7] are key components of the heterogeneous mononuclear phagocyte system, which is defined on the basis of common ontogeny and phagocytic activity [8]. The mononuclear phagocyte system provides the first line of innate immune responses against invading pathogens. In the peritoneal cavity, resident macrophages constitute the largest population of phagocytotic cells. However, the successful clearance of peritoneal infections critically depends on the rapid recruitment of neutrophils and IMs [9] from a specific shortlived CX 3 CR1 lo CCR2 + subset of peripheral blood monocytes [10].Peritoneal infections trigger the release of several CCR2-specific chemokines from peritoneal resident macrophages (prM ), such as CCL2, CCL7, and CCL13. However, significantly reduced numbers of recruited IMs and the inability to control toxoplasmosis in mice deficient for CCL2 or CCR2 suggest a critical nonredundant role for the CCR2/CCL2 axis in the clearance of peritoneal infections [11,12]. Aberrant...