An Enhanced Immune Response in Mice Lacking the Transcription Factor NFAT1

Abstract

Transcription factors of the NFAT family are thought to play a major role in regulating the expression of cytokine genes and other inducible genes during the immune response. The role of NFAT1 was investigated by targeted disruption of the NFAT1 gene. Unexpectedly, cells from NFAT1 -/- mice showed increased primary responses to Leishmania major and mounted increased secondary responses to ovalbumin in vitro. In an in vivo model of allergic inflammation, the accumulation of eosinophils and levels of serum immunoglobulin E were increased in NFAT1 -/- mice. These results suggest that NFAT1 exerts a negative regulatory influence on the immune response.

NFAT1 transcription factor regulates cell cycle progression and cyclin E expression in B lymphocytes

“…These results suggest that increased proliferation and Cyclin E overexpression in the B cell compartment contribute to the lymphocyte hyperproliferation phenotype observed in NFAT1-deficient mice. 39,40 We next addressed whether NFAT1 was able to bind the human Cyclin E1 and E2 promoters in B cells. Bioinformatics analysis of the proximal promoter regions indicated 6 putative NFAT-binding sites at each human promoter (Fig.…”

“…Deficiency of NFAT1 caused lymphocyte hyperproliferation and increased cell cycle rates both in vitro and in vivo, leading to splenomegaly and follicular B cell expansion. [38][39][40] However, most of these studies evaluated the responses from total lymph nodes or splenocytes to polyclonal stimuli and not specifically the stimulation of the B-cell compartment. Studies with purified B cells from NFAT1-deficient mice showed increased B-cell responsiveness and autoantibody production in the MD4/ soluble hen egg lysozyme (sHEL) transgenic model, indicating that NFAT1 may play a negative role in B cell activation.…”

The Duration of Nuclear Residence of NFAT Determines the Pattern of Cytokine Expression in Human SCID T Cells

“…That NFAT is indeed important for the expression of IL-2 in vivo was highlighted by the use of a selective peptide inhibitor of the NFAT-calcineurin interaction, that blocks the activation of all NFAT members and leads to decreased IL-2 expression in transfected Jurkat cells (59). Furthermore, none of the dominant features characteristic of these NF-AT-deficient mice, such as eosinophilia and increases in serum IgE (60), retarded thymic involution and massive germinal center formation (61), splenomegaly and hyperproliferation of T and B cells for the NFAT1 Ϫ/Ϫ and NFAT1 Ϫ/Ϫ /NFAT4 Ϫ/Ϫ mice (58,62), or defects in cardiac valve formation as in NFAT2 Ϫ/Ϫ mice (63, 64), were observed in our patients. On the other hand, characteristic phenotypic aspects of our patients, such as muscular hypotonia, dysplastic dental enamel, or early death from infections, were not observed in the NFAT1-, -2-, and -4-deficient mice, respectively.…”

Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance

“…It has been well characterized that redundancy within the NFAT family exists. In general, knocking out one NFAT protein results only in a mild phenotype, whereas knocking out two or more members leads to striking defects (45)(46)(47)(48)(49)(50)(51)(52)(53). The phenotypes of these mice seem to indicate that although NFAT1 and NFAT2 proteins regulate the expression of activation-induced genes, it is NFAT1 and NFAT4 that might be specifically involved in controlling cellular programs that lead to the negative regulation of T cell responses.…”