Two Faces of NFAT Transcription Factors in Lymphocytes—A Personal Account

The two NFAT transcription factors NFATc1 and NFATc2 are the most prominent Ca++-dependent TFs in the nuclei of activated peripheral lymphocytes. They control the activity of thousands of genes during immune responses. Although their structure and function show numerous things in common, their expression and activity differ markedly in most types of lymphocytes. Over the last 40 years, the work of our laboratory revealed a strong inducible transcription of the Nfatc1 gene upon lymphocyte (co-)activation, compared to the ‘tonic’ transcription of Nfatc2. This leads to the inducible expression of a short NFATc1 isoform that we designated as NFATc1/αA, which differs from longer NFATc1 proteins and NFATc2 by an individual N-terminal ‘α’ peptide and the absence of a C-terminal peptide of approximately 250 amino acid residues. While comprehensive experimental studies led to the conclusion that NFATc2 supports (i) apoptosis, (ii) the induction of anergy, and (iii) the ‘exhaustion’ of peripheral T cells, opposite conclusions can be derived from our studies of NFATc1/αA. This view on the ‘two faces’ of NFAT transcription factors will be presented in this review and discussed in the role of NFATs in cancerogenesis.