The optimum functioning of the immune system is crucial for human survival. The invading pathogens are encountered by the cells of the immune system, which include T-Cells, B-Cells, macrophages, neutrophils, basophils, eosinophils, endothelial cells, or mast cells. These cells have distinct roles in the immune system, and cell-to-cell communication among these cells is an indispensable prerequisite for the stimulation of the optimum immune response. In the process, cytokines serve as signal molecules for communication that are induced by several cell-signaling cascades. NFATs (Nuclear factors of activated T-Cells), a family of transcription factors expressed by diverse cell types of the immune system plays a pivotal role in the process. Originally described in T-Cells, NFATs have now been implicated in the activation of other cells constituting the immune system and play a key role in the expression of a wide array of immunologically important cytokines (Ref.1). The cytokines thus produced, possess both autocrine and paracrine functions, responsible for the activation of a highly concerted network of cell-cell communication and the subsequent immune response (Ref.2).
NFATs are basically calcium-dependent transcription factors, activated by stimulation of receptors coupled to calcium/calcineurin signals, such as the antigen receptors on T-Cells and B-Cells, Fc-Epsilon (Fc-Epsilon Receptors) on mast cells and basophils, the Fc-Gamma receptors on macrophages and NK cells, the platelet collagen receptors, and receptors coupled to heterotrimeric G-Proteins (Ref.3). NFATs serve to couple gene expression to changes in intracellular calcium levels and are regulated primarily at the level of their subcellular localization. In response to antigen receptor signaling, the calcium-regulated phosphatase, calcineurin acts to directly dephosphorylate NFAT proteins, causing their rapid translocation from the cytoplasm to the nucleus, where they cooperatively bind other transcription factors to induce gene expression. NFAT often functions at composite DNA elements by its interaction with Activating Protein-1 complex (a dimmer of c-Fos, c-Jun), GATA, and MEF2
(Mads Box Transcription Enhancer Factor-2), and the subsequent formation of a ternary complex induces expression of NFAT targets (cytokines and membrane proteins) (Ref.4). A highly choreographed series of gene regulations that follow the T-Cell activation and the subsequent NFAT signaling lie central to the lymphocyte cell-cell interactions.
An Antigen Presenting Cell within a cell-cell interaction presents antigenic peptides to the T-Cells. Antigen binding activates the TCR (T-Cell Receptor) that starts a signal chain leading to an increase in cytosolic Ca2+, both through the transient release of Ca2+ from intracellular stores and an influx of Ca2+ through specialized CRAC channels (Ca2+ Release Activated Ca2+ Channels), and subsequent activation of calcineurin. The activated calcineurin cleaves an inhibitory phosphate residue from the transcription factor NFAT. Consequently, NFAT is transported into the nucleus. This translocation process coupled to the subsequent active maintenance of NFAT in the nucleus compartment is critical for the expression of a number of immunologically important genes, including a wide array of cytokines: IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-13 (Interleukins), IFN-Gamma (Interferon-Gamma), TNF-Alpha (Tumor Necrosis Factor-Alpha), and GMCSF (Granulocyte-Macrophage Colony-Stimulating Factor), as well as several related membrane-bound proteins such as CD40L (CD40 Ligand), FasL (Fas Ligand) and CTLA4 (Cytotoxic T- Lymphocyte-Associated Antigen-4) (Ref.5). Most of these genes are dedicated to communication with other cell types. The secreted cytokines generally work locally, within the cell’s immediate environment and over a short period. Secreted IL-2 binds to CD25/IL-2R at the T-Cell surface to drive clonal expansion of the activated cell that induces autocrine proliferation. CD40L and FasL that are surface proteins, regulate the activation of the adjacent cells. FasL thus expressed, moves to the membrane and activates the nearby T-Cells that express its corresponding receptor. One role of CD40L in conjunction with BCR (B-Cell Receptor) signals and IL-4, IL-5, IL-6 and IL-10 is to activate NFAT signaling in B-Cells leading to immunoglobulin class switching and the production of IgE (Immunoglobulin-E) by some B-Cells. IgE in turn, activates NFATC1 translocation and function in mast cells and basophils through the FcEpsilonR leading to the production of an array of cytokines and chemokines that in turn influence T-Cell function. All these events are repeated in a cyclic fashion. Signaling in eosinophils also uses NFAT transcription complexes to activate cytokines and chemokines, which may be mediated by the cytokines expressed through NFAT signaling in other immune cells (Ref.2).
NFAT transcription complexes play critical roles in regulating the genes necessary for interactions with cells that do not have direct antigen receptors. By this means, NFAT signaling conveys the specificity of the TCR to other cell types involved in the immune response. Subsequently, NFAT signaling in other cell types in the immune system appears to produce positive feedback regulation that may be important for allergic and other immune responses. Understanding the biochemistry and logic behind these integrative processes will allow development of more selective and efficient pharmaceuticals that suppress, modify, or augment immune responses in autoimmunity, transplantation, allergy, vaccines, and cancer (Ref.6).