Abstract
In effector T and B cells immune receptor signals induce within minutes a rise of intracellular Ca++, the activation of the phosphatase calcineurin and the translocation of NFAT transcription factors from cytosol to nucleus. In addition to this first wave of NFAT activation, in a second step the occurrence of NFATc1/αA, a short isoform of NFATc1, is strongly induced. Upon primary stimulation of lymphocytes the induction of NFATc1/αA takes place during the G1 phase of cell cycle. Due to an auto-regulatory feedback circuit high levels of NFATc1/αA are kept constant during persistent immune receptor stimulation. Contrary to NFATc2 and further NFATc proteins which dampen lymphocyte proliferation, induce anergy and enhance activation induced cell death (AICD), NFATc1/αA supports antigen-mediated proliferation and protects lymphocytes against rapid AICD. Whereas high concentrations of NFATc1/αA can also lead to apoptosis, in collaboration with NF-κB-inducing co-stimulatory signals they support the survival of mature lymphocytes in late phases after their activation. However, if dysregulated, NFATc1/αA appears to contribute to lymphoma genesis and – as we assume – to further disorders of the lymphoid system. While the molecular details of NFATc1/αA action and its contribution to lymphoid disorders have to be investigated, NFATc1/αA differs in its generation and function markedly from all the other NFAT proteins which are expressed in lymphoid cells. Therefore, it represents a prime target for causal therapies of immune disorders in future.
Highlights
In effector T and B cells immune receptor signals induce within minutes a rise of intracellular Ca++, the activation of the phosphatase calcineurin and the translocation of Nuclear factor of activated T cells (NFAT) transcription factors from cytosol to nucleus
NFATc2 was shown to control B cell anergy in MD4ML5 mice [59] which are widely used to study B cell tolerance induction in vivo [60]. These findings suggest that NFATc factors in general exert a positive effect on E3 ubiquitin ligase expression and anergy induction [61]
NFATc1/αA lacks a 250 aa residues long Cterminal peptide with two sumoylation motifs, it contains a specific N-terminal peptide with several Ser/Thr and Pro residues, and its synthesis is strongly enhanced in effector T and B cells by immune receptor signals
Summary
The short NFATc1 protein NFATc1/αA differs in its structure and function from numerous, if not all other NFAT proteins. Several lines of evidence indicate that NFATc1/αA contributes – in collaboration with NF-κB factors - to the survival of effector lymphocytes. These properties favour NFATc1/αA as a target for treating disorders of the immune system. Endnotes aFor simplicity we use here and in all our other publications the term “NFAT factors” for members of a family of transcription factors which share a number of specific properties, e.g. the induction by calcineurin which dephosphorylates an array of phosphorylated sites upon cell activation. We are aware that the term NFAT (Nuclear Factor of Activated T Cells) is misleading since these transcription factors are expressed in numerous other cell types as well, and the acronym NFAT indicates the term factor. All authors read and approved the final manuscript
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