NF-AT signaling and leukocyte interactions
The optimum functioning of the immune system is crucial for human survival. Invading
pathogens are first encountered by the cells of the immune system, T-Cells, B-Cells,
macrophages, neutrophils, eosinophils, basophils, or mast cells. These cells have
distinct roles in the immune system, and cell-to-cell communication among them is an
indispensable prerequisite for the stimulation of the optimum immune response. In the
process, cytokines induced by several cell-signaling cascades serve as signal molecules
for communication. Nuclear factors of activated T-Cells
(NF-ATs), a family of transcription factors expressed by diverse cell
types of the immune system, play a pivotal role in the process. Originally described in
T-Cells, NF-ATs have now been implicated in the activation of other cells constituting
the immune system. They play a key role in the expression of a wide array of
immunologically important cytokines .
NF-ATs, essentially calcium-dependent transcription factors, are activated by
stimulation of receptors coupled to calcium/calcineurin signals, such as the antigen
receptors on T-Cells and B-Cells (TCR and
BCR), Fc-Epsilon receptors (e.g., Fc epsilon
R1) on mast cells and basophils, and receptors coupled to heterotrimeric
G-proteins (e.g., CCR3 on eosinophils) , . NF-ATs couple gene expression and changes
in intracellular calcium levels. They are regulated primarily at the level of their
subcellular localization. A highly choreographed series of gene regulations that follow
NF-AT signaling lie central to the leukocyte cell-cell interactions .
In cell-cell interactions, antigen Presenting Cells present antigenic peptides to the
T helper Cells via Major histocompatibility complex, class II
(MHC class II). MHC class II
peptides activate the T-Cell receptor
(TCR alpha/beta - CD3
complex) that starts a signal leading to the increase in cytosolic
Ca(II) through both the transient release of calcium from
intracellular stores, and influx of calcium through Ca(II)
channels. That leads to activation of the calcium-regulated phosphatase,
Calcineurin A. The activated Calcineurin A
cleaves an inhibitory phosphate residue from the transcription factor
NF-AT (e.g., NF-AT1 and
NF-AT2). Consequently, NF-AT is transported into the
nucleus, where it cooperates with other transcription factors for promoter binding. NF-AT
in T-Cells is critical for the expression of a number of immunologically important genes,
including interleukins IL-2,
IL-13, as well as several related membrane-bound proteins
such as CD40 Ligand (CD40L) and
Fas Ligand (FasL) , , .
Secreted IL-2 binds to IL-2
receptor at the T-Cell surface to drive clonal expansion of the activated
cell that induces autocrine proliferation .
FasL activates the adjacent T-Cells via the binding to
its receptor, FasR(CD95) .
CD40L activates nearby B-Cells that express corresponding
receptor CD40. In conjunction with
BCR, IL-4 signaling pathway
leads to the activation of several transcription factors, including Nuclear factor
kappa-B (NF-kB) and Signal transducer and activator of
transcription 6 (STAT6), that regulate immunoglobulin class
switching and the production of Immunoglobulin E
(IgE) by some B-Cells , , .
IgE in turn, activates
NF-AT1 translocation and function in mast cells and
basophils through the IgE receptor (Fc epsilon
R1) leading to production of an array of cytokines, including
IL-4, IL-5 and
IL-13 , . Fc
epsilon R1 pathway also leads to activation of the cytosolic phospholipase
A2 (cPLA2) that contributes to the secretion of leukotrienes
and prostaglandins, the main mediators of inflammatory response .
Haematopoietic cytokines (such as IL-5) stimulate the
proliferation and differentiation of eosinophils in the bone marrow and the release of
mature eosinophils into the blood .
IL-4 and IL-13 in turn,
activate epithelial cells and/or fibroblasts to release eosinophil-activating cytokines,
such as Chemokine (C-C motif) ligand 11 (Eotaxin), through
the Janus kinase 2 (JAK2)/
STAT6 pathway , , . These cytokines recruit eosinophils to the inflammatory focus in the tissue,
and induce intracellular signaling, mainly via Chemokine (C-C motif) receptor 3
(CCR3) activation, which leads to the prostaglandin and
leukotriene synthesis and also can use NF-AT1 transcription
complex to activate cytokines and chemokines , , , .
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