Role of NFAT in Regulation of the Immune Response


Pathway Description

NFATs are a family of transcription factors expressed in a variety of cell types of the immune system, and play a pivotal role in the process. NFATs are basically Calcium-dependent transcription factors, activated by stimulation of receptors coupled to Calcium-Calcineurin signals. Balanced activation of NFAT and Fos-Jun complex is known to be required for productive immune responses. Concomitant induction of NFAT and Fos-Jun requires concerted activation of two different signaling pathways: Calcium-Calcineurin, which promotes NFAT dephosphorylation, nuclear translocation and activation; and MAPK pathway which promotes the synthesis, phosphorylation and activation of membes of the Fos and Jun families of transcription factors, downstream of MAPK pathway.Activation of antigen receptors of the immune cells and the subsequent stimulation of costimulatory receptors in response to antigen presentation leads to activation of a series of signal transduction events mediated by several cytosolic tyrosine kinases and adaptor proteins like LAT, SLP76, and GRB2, SLP65 etc. and various kinases like ITK, BTK and SYK. These receptors contain unique cytoplasmic domains essential for downstream signaling, called ITAMs. One critical protein that is recruited to the adaptor proteins upon immunoreceptor stimulation is PLC-γ whereas, PLC-β is activated by the GPCRs. PLC is responsible for the production of the second messengers DAG and IP3. This event triggers the opening of CRAC channels at the plasma membrane, allowing influx of extracellular Ca2+, activating Calcineurin. This leads to the dephosphorylation of NFAT, allowing it to enter the nucleus for the induction of NFAT-mediated gene transcription. Effective phosphate removal by NFATs remain in the nucleus while Ca2+ is in elevated concentration and are rapidly phosphorylated and exported to the cytoplasm upon termination of Calcium signaling. Nuclear import of dephosphorylated NFATs is facilitated by Importins. In stimulated cells, an increase of intracellular Calcium ions activates Ccalcineurin to bring about dephosphorylation of NFAT. On the other hand, several kinases phosphorylate NFAT proteins and control their nuclear shuttling, including GSK3, CK1, p38 and JNK. CK1 docks at a conserved motif that is near the N-terminus of NFAT proteins, and it functions as both maintenance and an export kinase for SRR1. GSK3 functions as an export kinase. In stimulated active cells, it is inhibited by the PI3K/Akt pathway activated by CD28 costimulation. MAPKs differentially phosphorylate the first serine of SRR1 in the different NFAT proteins: p38 phosphorylates NFAT1, whereas JNK phosphorylates NFAT2. Rephosphorylation of NFAT by protein kinases brings about exposure of its NES and can be exported to the cytoplasm by the exportin CRM1.

The novel PKC isoform, PKC-θ is selectively expressed by the integration of TCR and CD28 costimulatory signals. Productive engagement of T-Cells by Antigen Presenting Cells results in recruitment of PKC-θ to the T-Cell-Antigen-Presenting Cell contact area-the Immunological Synapse, where it interacts with several signaling molecules like Fyn, Lck and ZAP70 to induce activation signals essential for the activation of transcription factors NF-κB, c-Jun and c-Fos. PKC-θ also cooperates with Calcineurin, in transducing signals leading to activation of c-Fos, c-Jun and NFAT.

NFAT1 induces T-Cell anergy if prevented from interacting with its transcriptional partners: c-Fos and c-Jun. Thus, a single transcription factor, NFAT, regulates two contrasting aspects of T-Cell function, mediating non-overlapping genetic programs of productive activation or anergy depending on the availability of Ca2+ and the presence or absence of its transcriptional partners.