Immune response - NF-AT signaling and leukocyte interactions

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 [1].

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) [2], [3]. 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 [4].

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-4, IL-5, IL-13, as well as several related membrane-bound proteins such as CD40 Ligand (CD40L) and Fas Ligand (FasL) [5], [6], [7].

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 [3].

FasL activates the adjacent T-Cells via the binding to its receptor, FasR(CD95) [4]. 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 [8], [9], [10].

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 [11], [12]. 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 [13].

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 [14].

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 [15], [16], [17]. 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 [4], [18], [19], [20].

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