Galectin-7 promotes proliferation and Th1/2 cells polarization toward Th1 in activated CD4+ T cells by inhibiting The TGFβ/Smad3 pathway
Introduction
Galectins (Gals) are a family of conserved β-galactoside-binding proteins that have been recognised as novel regulators of immune cells (Leffler et al., 2002; Liu and Rabinovich, 2005; Novak et al., 2014; Rabinovich et al., 2002). Galectin-7 (Gal-7) is preferentially expressed in stratified epithelia and in various types of cancer, and is associated with cell apoptosis and proliferation (Bernerd et al., 1999; Cao et al., 2003; Kuwabara et al., 2002; Madsen et al., 1995).
Our previous studies have revealed that Gal-7 expression increased significantly in cardiac allografts compared with cardiac isografts in mice. Additionally, the majority of Gal-7-positive cells in the allografts comprised infiltrating lymphocytes and vascular endothelial cells. Subsequently, we reported that the percentage of Gal-7-positive CD4+ T-cell is significantly higher in allograft group compared to isograft group (Luo et al., 2013). We have also identified increased Gal-7 expression in serum from renal allograft recipients compared with normal volunteers (Gao et al., 2009). In addition, Inagaki and colleagues have showed that Gal-7 as a transcriptional regulator antagonises TGFβ-mediated effects by interacting with Smad3 in hepatocytes (Inagaki et al., 2008). TGFβ is essential for attenuating CD4+ T-cell activation necessary to maintain immune homeostasis (Worthington et al., 2012). These findings suggest that Gal-7 is associated with the allograft rejection and CD4+ T-cell responses. However, the effects and functional mechanism of Gal-7 in the process of CD4+ T-cell response still remain unknown.
Rossi et al. (2008) have confirmed that Gal-7 binds to the glycosylation of TCR/CD3 complex on T-cell surface. The glycosylation differences may have an impact on T-cell proliferation and differentiation (Kjer-Nielsen et al., 2004). The TCR/CD3 complex is one of the important factors affecting the Th1 and Th2 cells immune responses (Mannie, 1997). Th1 cells induce IFN-γ production to inhibit tumor formation and regulate immune responses and inflammation. Th2 cells produce IL-4, thus mediating the activation of the allergy or humoral immune response. It has been found that the imbalance of Th1/Th2 responses may lead to a variety of immune diseases. The excessive amounts of IFN-γ have been associated with Th1-mediated immune disorders, such as allograft rejection and several autoimmune diseases (Murphy and Reiner, 2002).
To examine the role of Gal-7 protein in CD4+ T-cell responses, CD4+ T-cell proliferation and phenotypic changes of CD4+ T cells were analysed by flow cytometry to further investigate the role of Gal-7 in the Thl and Th2 cells responses. The cytokines of CD4+ T cells were examined by quantitative real-time PCR. To study the mechanism of Gal-7 in the process of T-cell response, subcellular localisation and expression of Smad3 were determined by immunofluorescence staining and Western blot analyses.
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Mice
Male BALB/c (H-2d) mice were obtained from Vital River Laboratories, China. Animals were fed under controlled conditions. In addition, all animals were housed in an environment with temperature of 22 ± 1 °C, relative humidity of 50 ± 1% and a light/dark cycle of 12/12 h. Furthermore, all animal studies (including the mice euthanasia procedure) were done in compliance with the regulations and guidelines of Tongji Medical College institutional animal care and were conducted according to the
No cell proliferation of resting CD4+ T-lymphocytes was observed following the administration of Gal-7
We analysed the effects of Gal-7 on resting CD4+ T-cell proliferation. The CFSE-labelled CD4+ T cells were administered with PBS or different concentrations of Gal-7 for 5 days. Cellular suspensions were analysed to determine the level of CD4+ T-cell proliferation using flow cytometry. To sum up, no proliferation of CD4+ T-cell was observed in any group (Fig. 1, data not shown), which suggests that Gal-7 did not enhance the proliferation of resting CD4+ T-cell.
Gal-7 enhanced the proliferation of activated CD4+ T lymphocytes
The effects of Gal-7 on the
Discussion
Galectins exert important effects on the immune system by manipulating T-cell apoptosis and proliferation (Leffler et al., 2002; Liu and Rabinovich, 2005; Novak et al., 2014; Rabinovich et al., 2002). Gal-1 modulates Th1 and Th17 cells growth and apoptosis (Toscano et al., 2007), while Gal-2 promotes apoptosis in activated T cells (Sturm et al., 2004). Gal-9 has been shown to induce activated Th1 cells apoptosis (Zhu et al., 2005). Our group has revealed that Gal-9 can inhibit T-cell
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
This study was supported by National Natural Science Foundation of China (nos. 81500436, 81671582).
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