ABSTRACT
Emerging evidence underscores the importance of CD8+ T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8+ T cells (CD8+CXCR5+ T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8+CXCR5+ T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8+CXCR5+ T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8+CXCR5+ T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8+CXCR5+ T cells into naïve mice confirmed their ability to enhance the production of anti-MOG35-55 antibodies and contribute to the disease progression. Consequently, CD8+CXCR5+ T cells may play a role in CNS demyelination through heightening humoral immune responses.
ABSTRACT
BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive system, ranking third for morbidity and mortality worldwide. At present, no effective control method is available for this cancer type. In tumor cells, especially iron metabolization, is necessary for its growth and proliferation. High levels of iron are an important feature to maintain tumor growth; however, the overall mechanism remains unclear. METHODS: We used western blotting, immunohistochemistry (IHC) and real-time quantitative PCR to analyze the expression of IGF2BP2 in cell lines and tissues. Further, RNA-sequencing, RNA immunoprecipitation and methylated RNA immunoprecipitation experiments explored the specific binding of target genes. Moreover, the RNA stability assay was performed to determine the half-life of genes downstream of IGF2BP2. In addition, the Cell Counting Kit-8, colony formation assay, 5-ethynyl-2'-deoxyuridine assay and flow cytometry were used to evaluate the effects of IGF2BP2 on proliferation and iron metabolism. Lastly, the role of IGF2BP2 in promoting CRC growth was demonstrated in animal models. RESULTS: We observed that IGF2BP2 is associated with iron homeostasis and that TFRC is a downstream target of IGF2BP2. Further, overexpression of TFRC can rescue the growth of IGF2BP2-knockdown CRC cells. Mechanistically, we determined that IGF2BP2 regulates TFRC methylation via METTL4, thereby regulating iron metabolism and promoting CRC growth. Furthermore, using animal models, we observed that IGF2BP2 promotes CRC growth. CONCLUSION: IGF2BP2 regulates TFRC mRNA methylation via METTL4, thereby regulating iron metabolism and promoting CRC growth. Our study highlights the key roles of IGF2BP2 in CRC carcinogenesis and the iron transport pathways.
