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Follicular T helper (T(FH)) cells are specialized T cells that support B cells, which are essential for humoral immunity. T(FH) cells express the transcription factor B‐cell lymphoma 6 (Bcl‐6), chemokine (C‐X‐C motif) receptor (CXCR) 5, the surface receptors programmed cell death protein 1 (PD‐1) and inducible T‐cell costimulator (ICOS), the cytokine IL‐21 and other molecules. The activation, proliferation and differentiation of T(FH) cells are closely related to dynamic changes in cellular metabolism. In this review, we summarize the progress made in understanding the development and functional differentiation of T(FH) cells. Specifically, we focus on the regulatory mechanisms of T(FH) cell functional differentiation, including regulatory signalling pathways and the metabolic regulatory mechanisms of T(FH) cells. In addition, T(FH) cells are closely related to immune‐associated diseases, including infections, autoimmune diseases and cancers.

Mammalian STE20-like protein kinases (MST), including MST1, MST2, MST3, and MST4, belong to the germinal center kinase (GCK) family. Kinase MST1/2 is an important component of the Hippo pathway in regulating cell proliferation, tissue homeostasis, and organ development. Recent studies have shown that Hippo kinase MST1/2 plays a crucial role in immune-associated diseases, which has attracted extensive attention of researchers. This review summarizes recent research on Hippo kinases MST1/2 in regulating the function of immune cells in innate and adaptive immune systems, and also includes its regulatory role and significance in cancer, infection, and autoimmune diseases.

Simple Summary Myeloid-Derived Suppressor Cells (MDSCs) have been regarded as the main promoters of cancer development in recent years. They can protect tumor cells from being eliminated by neutralizing the anti-tumor response mediated by T cells, macrophages and dendritic cells (DCs). Therefore, different treatment methods targeting MDSCs, including chemotherapy, radiotherapy and immunotherapy, have been developed and proven to effectively inhibit tumor expansion. Herein, we summarize the immunosuppressive role of MDSCs in the tumor microenvironment and some effective treatments targeting MDSCs, and discuss the differences between different therapies. Abstract Myeloid-derived suppressor cells (MDSCs), which are activated under pathological conditions, are a group of heterogeneous immature myeloid cells. MDSCs have potent capacities to support tumor growth via inhibition of the antitumoral immune response and/or the induction of immunosuppressive cells. In addition, multiple studies have demonstrated that MDSCs provide potential therapeutic targets for the elimination of immunosuppressive functions and the inhibition of tumor growth. The combination of targeting MDSCs and other therapeutic approaches has also demonstrated powerful antitumor effects. In this review, we summarize the characteristics of MDSCs in the tumor microenvironment (TME) and current strategies of cancer treatment by targeting MDSCs.

Macrophages differentiated into a classically activated (M1) or alternatively activated phenotype (M2) in infection and tumor, but the precise effects of glycolysis and oxidative phosphorylation (OXPHOS) metabolic pathway remain unclear. Herein, the effects of glycolysis or OXPHOS on macrophage polarizations were investigated using a pharmacological approach in mice. 2-Deoxy-D-glucose (2-DG) treatments, which blocks the key enzyme hexokinase of glycolysis, efficiently inhibits a specific switch to M1 lineage, decreasing the secretion of pro-inflammatory cytokines and expressions of co-stimulatory molecules associated with relieving infectious inflammation in vitro and in vivo. Glycolytic activation through the hypoxia-inducible factor-1α (HIF-1α) pathway was required for differentiation to the M1 phenotype, which conferred protection against infection. Dimethyl malonate (DMM) treatment, which blocks the key element succinate of OXPHOS, efficiently inhibits a specific switch to M2 lineage when macrophages receiving M2 stimulation, decreasing the secretion of anti-inflammatory cytokine and CD206 expressions. Mitochondrial dynamic alterations including mitochondrial mass, mitochondrial membrane potential (Dym) and ROS productions were critically for differentiation to the M2 phenotype, which conferred protection against anti-tumor immunity. Glycolysis is also required for macrophage M2 differentiation. Thus, these data provide a basis for a comprehensively understanding the role of glycolysis and OXPHOS in macrophage differentiation during anti-infection and anti-tumor inflammation.

T cells can be categorized into functionally diverse subpopulations, which include Th1, Th2, Th9, Th17, Th22, and Tfh cells and Foxp3+ Tregs, based on their role in maintaining normal immune homeostasis and affecting pathological immune-associated diseases. Among these subpopulations, Th9 cells are relatively new, and less is known about their signaling and effects on tumor immunity. Recently, some studies have focused on regulation of the IL-9/IL-9R signaling pathway and Th9 cell differentiation and their roles in tumor environments. Herein, we summarize recent progress in understanding the regulatory signaling of IL-9 and Th9 cells and their critical roles and mechanisms in antitumor immunity.

Follicular helper T (TFH) cells are critical for germinal center (GC) formation and are responsible for effective B cell-mediated immunity, metabolic signaling is an important regulatory mechanism for the differentiation of TFH cells. However, the precise roles of hypoxia inducible factor (HIF) 1&alpha, dependent glycolysis and oxidative phosphorylation (OXPHOS) metabolic signaling remain unclear in TFH cell differentiation. Herein, we investigated the effects of glycolysis and OXPHOS on TFH cell differentiation and GC responses using a pharmacological approach in mice under a steady immune status or an activated immune status, which can be caused by foreign antigen stimulation and viral infection. GC and TFH cell responses are related to signals from glycolytic metabolism in mice of different ages. Foreign, specific antigen-induced GC, and TFH cell responses and metabolic signals are essential upon PR8 infection. Glycolysis and succinate-mediated OXPHOS are required for the GC response and TFH cell differentiation. Furthermore, HIF1&alpha, is responsible for glycolysis- and OXPHOS-induced alterations in the GC response and TFH cell differentiation under steady or activated conditions in vivo. Blocking glycolysis and upregulating OXPHOS signaling significantly recovered TFH cell differentiation upon PR8 infection and ameliorated inflammatory damage in mice. Thus, our data provide a comprehensive experimental basis for fully understanding the precise roles of HIF1&alpha, mediated glycolysis and OXPHOS metabolic signaling in regulating the GC response and TFH cell differentiation during stable physiological conditions or an antiviral immune response.

The therapeutic effects of glucocorticoids on colitis and colitis-associated cancer are unclear. In this study, we investigated the therapeutic roles of glucocorticoids in acute experimental ulcerative colitis and colitis-associated cancer in mice and their immunoregulatory mechanisms. Murine acute ulcerative colitis was induced by dextran sulfate sodium (DSS) and treated with dexamethasone (Dex) at different doses. Dex significantly exacerbated the onset and severity of DSS-induced colitis and potentiated mucosal inflammatory macrophage and neutrophil infiltration, as well as cytokine production. Furthermore, under inflammatory conditions, the expression of the glucocorticoid receptor (GR) did not change significantly, while mammalian target of rapamycin (mTOR) signaling was higher in colonic epithelial cells than in colonic immune cells. The deletion of mTOR in intestinal epithelial cells, but not that in myeloid immune cells, in mice significantly ameliorated the severe course of colitis caused by Dex, including weight loss, clinical score, colon length, pathological damage, inflammatory cell infiltration and pro-inflammatory cytokine production. These data suggest that mTOR signaling in intestinal epithelial cells, mainly mTORC1, plays a critical role in the Dex-induced exacerbation of acute colitis and colitis-associated cancer. Thus, these pieces of evidence indicate that glucocorticoid-induced mTOR signaling in epithelial cells is required in the early stages of acute ulcerative colitis by modulating the dynamics of innate immune cell recruitment and activation.