Abstract
The early differentiation of T helper (Th) cells is a tightly controlled and finely balanced process, which involves several factors including cytokines, transcription factors and co-stimulatory molecules. Recent studies have shown that in addition to the regulation of apoptosis, caspase activity is also needed for Th cell proliferation and activation and it might play a role in Th cell differentiation. The isoforms of the cellular FLICE inhibitory protein (c-FLIP) are regulators of CASPASE-8 activity and the short isoform, c-FLIPS, has been shown to be up-regulated by IL-4, the Th2 driving cytokine. In this work, we have studied the expression and functional role of three c-FLIP isoforms during the early Th cell differentiation. Only two of the isoforms, c-FLIPS and c-FLIPL, were detected at the protein level although c-FLIPR was expressed at the mRNA level. The knockdown of c-FLIPL led to enhanced Th1 differentiation and elevated IL-4 production by Th2 cells, whereas the knockdown of c-FLIPS diminished GATA3 expression and IL-4 production by Th2 cells. In summary, our results provide new insight into the role of c-FLIP proteins in the early differentiation of human Th cells.
Highlights
T helper (Th) cells have an important role in body’s defense against extra- and intracellular pathogens
T cell receptor (TCR) activation leads to the activation of several pathways, such as Ras/extracellular signal-regulated kinase (ERK), Nuclear factor of activated T cells (NFAT) and Nuclear factor kappa enhancer binding protein (NF-kB) pathways, which are important for the initial activation and for the ability of T cells to differentiate into functional subtypes
All isoforms were found to be rapidly up-regulated by TCR activation alone and the levels of cFLIPL, c-FLIP short (c-FLIPS) and c-FLIP raji (c-FLIPR) mRNA were increased already 2 h after the initiation of the culture compared with Th precursor (Thp) cells
Summary
T helper (Th) cells have an important role in body’s defense against extra- and intracellular pathogens. Different Th subtypes are characterized by the expression of different transcription factors, cell surface receptors and the secretion of cytokines. The first-characterized and most widely studied subtypes are Th1 and Th2 cells, which are important for cell-mediated immunity eradicating intracellular pathogens and humoral responses, respectively. Naive Thp cells secrete IFNc in response to TCR activation, which is mediated by NFAT and NF-kB transcription factors [2,3]. IFNc induces the differentiation of Th1 cells through STAT1 signaling [4]. These signaling pathways lead to the expression of TBET [5,6]. Once the expression of IL12Rb2 is up-regulated, IL-12 is able to activate STAT4, an important inducer of IFNc and IL-12Rb2 expression [9,10,11,12]
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