Chen Dong

Northwestern Polytechnical University | NWPU · Department of Electronic and Communication Engineering

TCRαβ+CD8αα+ intraepithelial lymphocytes (CD8αα+ αβ IELs) are a specialized subset of T cells in the gut epithelium that develop from thymic agonist selected IEL precursors (IELps). The molecular mechanisms underlying the selection and differentiation of this T cell type in the thymus are largely unknown. Here, we found that Bcl6 deficiency in αβ T...

T follicular helper (Tfh) cells, essential for germinal center reactions, are not identical, with different phenotypes reported. Whether, when, and how they generate memory cells is still poorly understood. Here, through single-cell RNA-sequencing analysis of CXCR5⁺Bcl6⁺ Tfh cells generated under different conditions, we discovered, in addition to...

Overcoming CD8 ⁺ T cell exhaustion is critical in cancer immunotherapy. Recently, an intratumor stem/progenitor-like CD8 ⁺ T cell (T prog cell) population that mediates the persistence of antitumor responses has been defined, which can further develop into a terminally differentiated CD8 ⁺ T cell (T term cell) subpopulation with potent cytotoxic fu...

The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (Tfh) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature type 2 conventional dendritic cells (cDC2s) and Tfh cells were found within T cell zones of colon...

Background As an important early source of IL-17A and IL-22 in immune responses, type 3 innate lymphoid cells (ILC3s) are critically regulated by the transcription factor retinoic-acid-receptor-related orphan receptor gamma t (RORγt). Previously, we have identified a crucial role of the conserved non-coding sequence 9 (CNS9), located at +5,802 to +...

In cancer, persistent antigens drive CD8+ T cell differentiation into exhausted progenitor (Texprog) and terminally exhausted (Texterm) cells. However, how the extrinsic and intrinsic regulatory mechanisms cooperate during this process still remains not well understood. Here, we found that STAT3 signaling plays essential roles in promoting intratum...

Innate lymphoid cells (ILC) are similar to T helper (Th) cells in expression of cytokines and transcription factors. For example, RORγt is the lineage-specific transcription factor for both ILC3 and Th17 cells. However, the ILC counterpart for BCL6-expressing T follicular helper (Tfh) cells has not been defined. Here, we report that in the ILC comp...

Antibodies are crucial in host defenses as well as in allergic diseases. T follicular helper (TFH) cells play essential roles in germinal center reactions by facilitating B-cell differentiation and immunoglobulin affinity maturation and isotype switching. Although TFH cells have a unique gene transcription program and regulatory network, recently t...

Aberrant RNA splicing in keratinocytes drives inflammatory skin disorders. In the present study, we found that the RNA helicase DDX5 was downregulated in keratinocytes from the inflammatory skin lesions in patients with atopic dermatitis and psoriasis, and that mice with keratinocyte-specific deletion of Ddx5 ( Ddx5 ∆KC ) were more susceptible to c...

Forkhead box O transcriptional factors, especially FoxO1 and FoxO3a, play critical roles in physiologic and pathologic immune responses. However, the function of FoxO4, another main member of the FoxO family, in lymphoid cells is still poorly understood. Here, we showed that loss of FoxO4 in T cells augmented IFN-γ production of Th1 cells in vitro....

RORγt is the lineage-specific transcription factor for T helper 17 (T H 17) cells and an attractive drug target for treating T H 17-associated diseases. Although the critical role of RORγt in early T H 17 cell differentiation has been well recognized, its function in mature T H 17 cell maintenance remains largely unknown. Here, we show that genetic...

Transforming growth factor-β is well known to restrain cytotoxic T cell responses to maintain self-tolerance and to promote tumor immune evasion. In this study, we have investigated the role of SMAD4, a core component in the TGF-β signaling pathway, in CD8+ T cells. Unexpectedly, we found that SMAD4 was critical in promoting CD8+ T cell function in...

There are many potential immunotherapeutic targets for cancer immunotherapy, which should be assessed for efficacy before they enter clinical trials. Here we established an ex vivo cultured patient-derived tumor tissue model to evaluate antitumor effectiveness of one VISTA inhibitor, given that our previous study showed that VISTA was selectively h...

Cellular and humoral immunity are both important in host defense against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although defects in SARS-CoV-2-specific T cell immunity have been found in patients with severe lung pathology, it is still largely unclear whether virus-specific T cells are sufficient for host protection. Here, we...

T follicular helper (Tfh) cells are critical in providing help for B cells in the germinal center reaction. Tfh cell plasticity, especially with regard to their expression of effector Th cytokines, has been described, but lacks in-depth analysis with genetic approaches. In this study, we systemically compared transcriptomic profiles of Tfh cells de...

Cellular communication in the tumor microenvironment is crucial for T cell activation; however, the molecular features of the T cell–antigen-presenting cell interaction are still poorly understood. A new study utilizes RNA sequencing of physically interacting cells to reveal that PD-1+CXCL13+ helper T cells in tumors, primed by dendritic cells, are...

Cellular and humoral immunity are both important in host defense against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although defects in SARS-CoV-2-specific T cell immunity have been found in patients with severe lung pathology, it is still largely unclear whether virus-specific T cells are sufficient for host protection. Here, we...

Background Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD). Methods This single centre, double-blind, randomised,...

T follicular helper (Tfh) cells play essential roles in regulating humoral immunity, especially germinal center reactions. However, how CD4+ T cells integrate the antigenic and costimulatory signals in Tfh cell development is still poorly understood. Here, we found that phorbol 12-myristate 13-acetate (PMA) + ionomycin (P+I) stimulation, together w...

Inflammatory bowel disease (IBD) is multi-factorial chronic intestinal inflammation driven by pathogenic T cells, among which a large portion of patients are resistant to current anti-inflammatory regimes. The mechanisms underlying colitis pathogenicity and drug resistance are not fully understood. Here, we demonstrate that RORα is highly expressed...

During germinal center (GC) reactions, activated B cells undergo clonal expansion and functional maturation to produce high-affinity antibodies and differentiate into plasma and memory cells, accompanied with class-switching recombination (CSR) and somatic hypermutation (SHM). Activation-induced cytidine deaminase (AID) is responsible for both CSR...

Background Multiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8⁺ tumor-infiltrating lymphocytes (TILs) remain unclear. Methods To determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8...

The interleukin (IL)-17 family, consisting of six members, promotes host defense but can in some context promote the development of autoimmune disease. Here, we examined the role of IL-17D, a poorly understood member in the IL-17 family. IL-17D was expressed primarily by colonic epithelial cells. Il17d-/- mice were more susceptible to acute colitis...

The high infection rate and rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) make it a world-wide pandemic. Individuals infected by the virus exhibited different degrees of symptoms, and most convalescent individuals have been shown to develop both cellular and humoral immune responses. However, virus-specific adaptive i...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

SOSTDC1 for germinal center regulation T follicular helper (T FH ) cells are CD4 ⁺ T cells that facilitate B cell antibody production and B cell memory responses in the germinal centers (GCs) of lymphoid organs. These activities are in turn restrained by T follicular regulatory (T FR ) cells, a population of T cells with unclear origins. Wu et al....

IL-9-producing CD4⁺ T cells have been considered to represent a distinct T helper cell (TH cell) subset owing to their unique developmental programme in vitro, their expression of distinct transcription factors (including PU.1) and their copious production of IL-9. It remains debatable whether these cells represent a truly unique TH cell subset in...

The World Health Organization has declared SARS-CoV-2 virus outbreak a world-wide pandemic. Individuals infected by the virus exhibited different degrees of symptoms, the basis of which remains largely unclear. Currently, though convalescent individuals have been shown with both cellular and humoral immune responses, there is very limited understan...

Bacterial infection or abnormal colonization in the gastrointestinal system is associated with subsets of inflammatory bowel disease and colorectal cancer. Here we demonstrated essential roles of ubiquitin-specific protease 25 (USP25) in experimental colitis, bacterial infections and colon cancer. Knockout or pharmacologic inhibition of USP25 poten...

RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells whose upregulation in developing Th17 cells is critically regulated by interleukin-6 (IL-6) and TGF-β, the molecular mechanisms of which remain largely unknown. Here we identified conserved non-coding sequences (CNSs) 6 and 9 at the Rorc gene, essential for its expressi...

In October 2005, we, alongside the laboratory of Casey Weaver, identified a third type of helper T cells that produce the cytokine IL-17, important for the regulation of tissue inflammation.

Most patients diagnosed with hepatocellular carcinoma (HCC) present with advanced or metastatic disease. The lack of therapeutic options in the treatment of advanced HCC accounts for its high mortality and recurrence rate. HCC is known as an immunogenic tumor, which develops in chronically inflamed livers. Anti-PD-1/PD-L1 antibodies (immune checkpo...

The World Health Organization has declared SARS-CoV-2 virus outbreak a world-wide pandemic. However, there is very limited understanding on the immune responses, especially adaptive immune responses to SARS-CoV-2 infection. Here, we collected blood from COVID-19 patients who have recently become virus-free and therefore were discharged, and detecte...

Citrobacter rodentium colonizes at the colon and causes mucosal inflammation in mice. Previous studies have revealed the importance of the innate and adaptive immune response for controlling C. rodentium infection. In the present study, we examined the role of T follicular helper (Tfh) cells in intestinal C. rodentium infection using mice with Bcl6...

Fever, an evolutionarily conserved physiological response to infection, is also commonly associated with many autoimmune diseases, but its role in T cell differentiation and autoimmunity remains largely unclear. T helper 17 (Th17) cells are critical in host defense and autoinflammatory diseases, with distinct phenotypes and pathogenicity. Here, we...

CXCR5 mediates homing of both B and follicular helper T (TFH) cells into follicles of secondary lymphoid organs. We found that CXCR5+CD8+ T cells are present in human tonsils and follicular lymphoma, inhibit TFH-mediated B cell differentiation, and exhibit strong cytotoxic activity. Consistent with these findings, adoptive transfer of CXCR5+CD8+ T...

T follicular helper (Tfh) cells provide essential help to B cells in germinal center (GC) reactions. Bcl6 is the obligatory lineage transcription factor in Tfh cells. Here, we examined the molecular pathways that induce Bcl6 gene expression and underscore Bcl6-dependent function during Tfh cell commitment. Integration of genome-wide Bcl6 occupancy...

B7-H4 is a negative regulatory B7 family member. We investigated the role of host and donor B7-H4 in regulating acute graft-versus-host disease (GVHD). Allogeneic donor T cells infused into B7-H4-/- versus WT recipients markedly accelerated GVHD-induced lethality. Chimera studies pointed toward B7-H4 expression on host hematopoietic cells as more c...

Although PD-L1/PD-1 blockade therapy has been approved to treat many types of cancers, the majority of patients with solid tumors do not respond well, but the underlying reason remains unclear. Here, we studied ovarian cancer (OvCa), a tumor type generally resistant to current immunotherapies, to investigate PD-1-independent immunosuppression. We f...

T helper 17 (TH17) cells and interleukin-17A (IL-17A) produced by them are critical in autoinflammatory diseases, such as psoriasis. IL-17A has been shown to signal through IL-17 receptor A/IL-17 receptor C (IL-17RA/IL-17RC) complex to drive inflammatory responses. However, in a psoriasis model, we found that Il17rc deficiency did not completely am...

The B7 family members are critical in positive and negative regulation of immune responses by engaging various lymphocyte receptors. B7-H4 is a member of the B7 family that can negatively regulate T cell function. We investigated the role of host and donor B7-H4 in regulating acute graft-versus-host disease (GVHD). Allogeneic donor T cells infused...

Nonalcoholic fatty liver disease is currently the most common liver disease and is a leading cause of liver‐related morbidity and mortality. However, its pathogenesis remains largely unclear. We previously showed that mice deficient in mitogen‐activated protein kinase (MAPK) phosphatase 5 (MKP5) spontaneously developed insulin resistance and glucos...

T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction2. However, the molecular mechanisms that underlie this dy...

Eomes, a T-box transcription factor, is known important for both function and homeostasis of effector and memory T cells, but was recently also implicated in CD8⁺ T cell exhaustion. However, whether and how Eomes might regulate effector functions or exhaustion of CD8⁺ T cells, especially in the tumor setting, is unknown. Here we first show, as tumo...

Colorectal carcinoma (CRC) is one of the most common malignancies in the world. PD-1/PD-L1 inhibitors have benefited cancer patients with multiple tumor types. However, their efficacy for CRC is low and this treatment in melanoma patients results in adaptive resistance through upregulation of VISTA, another checkpoint inhibitory pathway. Thus, ther...

Transforming growth factor–β (TGF-β) regulates reciprocal regulatory T cell (T reg) and T helper 17 (Th17) differentiation, the underlying mechanism of which is still not understood. Here, we report that tripartite motif-containing 33 (Trim33), a modulator of TGF-β signaling that associates with Smad2, regulates the proinflammatory function of Th17...

The antitumor effector T helper 1 (Th1) and Th17 cells represent two T cell paradigms: short-lived cytolytic Th1 cells and "stem cell-like" memory Th17 cells. We report that Th9 cells represent a third paradigm-they are less-exhausted, fully cytolytic, and hyperproliferative. Only tumor-specific Th9 cells completely eradicated advanced tumors, main...

Chronic obstructive pulmonary disease (COPD) is currently the third largest cause of human mortality in the world after stroke and heart disease. COPD is characterized by sustained inflammation of the airways, leading to destruction of lung tissue and declining pulmonary function. The main risk factor is known to be cigarette smoke currently. Howev...

T helper 17 (Th17) cell development is programmed by the orphan nuclear receptor RORγt, but the underlying mechanism is not well understood. Nuclear receptor-mediated transcriptional activation depends on coactivators. Here, we show that steroid receptor coactivator-3 (SRC-3) critically regulates Th17 cell differentiation. Reduced incidence of expe...

CD8 ⁺ T cells can be polarized into IL-9–secreting (Tc9) cells. We previously showed that adoptive therapy using tumor-specific Tc9 cells generated stronger antitumor responses in mouse melanoma than classical Tc1 cells. To understand why Tc9 cells exert stronger antitumor responses, we used gene profiling to compare Tc9 and Tc1 cells. Tc9 cells ex...

Epigenetic regulation is important for T-cell fate decision. Although STAT3 is known to initiate Th17 differentiation program, the downstream mechanism is unclear. Here we show that Tripartite motif containing 28 (Trim28) expression in Th17 cells is required for Th17-mediated cytokine production and experimental autoimmune diseases. Genome-wide occ...

The molecular mechanisms whereby CD8+T cells become "exhausted" in the tumor microenvironment remain unclear. Programmed death ligand-1 (PD-L1) is upregulated on tumor cells and PD-1-PD-L1 blockade has significant efficacy in human tumors; however, most patients do not respond, suggesting additional mechanisms underlying T cell exhaustion. B7 super...

Psoriasis is a chronic autoinflammatory skin disease. Although interleukin-17, derived from lymphocytes, has been shown to be critical in psoriasis, the initiation and maintenance of chronic skin inflammation has not been well understood. IL-25 (also called IL-17E), another IL-17 family cytokine, is well known to regulate allergic responses and typ...

T follicular regulatory (Tfr) cells are a new subset of regulatory T (T reg) cells localized in the germinal center to limit the humoral response. Until now, the physiological function of Tfr cells has been largely unknown. In this study, we developed a Bcl6 fl/fl Foxp3Cre mouse to analyze the function of Tfr cells in immune and autoimmune response...

Th17 cells are potent mediators in autoimmune diseases, and RORγt is required for their development. Recent studies have shown that RORγt⁺ Treg cells in the gut regulate intestinal inflammation by inhibiting effector T cell function. In the current study, we report that RORγt⁺ Treg cells were also found in lymph nodes following immunization. Not on...

Background: Allergic asthma is a heterogeneous chronic inflammatory disease in the airway with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific Th2 cells and Th17 cells, respectively. Successful treatment of allergic asthma will therefore require suppression of both Th2 and Th17 cells. Objective: We sought to in...

The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecul...

SUMOylation is an important posttranslational modification that regulates protein function in diverse biological processes. However, its role in early T cell development has not been genetically studied. UBC9 is the only E2 enzyme for all SUMOylation. In this study, by selectively deleting Ubc9 gene in T cells, we have investigated the functional r...

As potent pro-inflammatory mediators, cytokines in the interleukin-17 (IL-17) family play crucial roles in inflammation, autoimmunity, and host defense. In the past decade, substantial progress was made in the identification of IL-17-producing cell subsets as well as the new functions of IL-17 in diseases. Here we summarize members of the IL-17 and...

Autoimmune hepatitis is a worldwide health problem and significant cause of mortality. However, the disease etiology is largely unknown, which accounts for ineffective treatment and uncontrolled disease progression. In this study, we demonstrated the functional importance of the IL-17C/IL-17RE axis in Con A-induced hepatitis. Elevated IL-17C expres...

Metastasis is the leading cause of death in breast cancer patients. However, the mechanisms underlying metastasis are not well understood and there is no effective treatment in the clinic. Here, we demonstrate that in MMTV-PyMT, a highly malignant spontaneous breast tumor model, IL-25 (also called IL-17E) was expressed by tumor-infiltrating CD4⁺ T...

T helper 17 (Th17) cells are key players in autoimmune diseases. However, the roles of non-coding RNAs in Th17 cell development and function are largely unknown. We found that deletion of the endoribonuclease-encoding Dicer1 specifically in Th17 cells protected mice from experimental autoimmune encephalomyelitis. We found that the Dicer1-regulated...

T follicular helper (Tfh) cell is a unique T cell subset specialized in promoting humoral immunity. B-cell lymphoma 6 protein (Bcl6) has been identified as an obligatory transcription factor in Tfh cells; however, the molecular mechanism underlying Bcl6 function remains largely unknown. Here, we defined Bcl6 target genes in Tfh cells by analyzing g...

Background: Food-mediated allergic reactions have emerged as a major health problem. The underlying mechanisms that promote uncontrolled type 2 immune responses to dietary allergens in the gastrointestinal tract remain elusive. Objective: We investigated whether altering IL-25 signaling enhances or attenuates allergic responses to food allergens...

Inflammatory cytokines are key regulators of immune responses. Persistent and excessive production of inflammatory cytokines underscores the development of autoimmune diseases. Therefore, neutralizing inflammatory cytokines or antagonizing their receptor function is considered as a useful therapeutic strategy to treat autoimmune diseases. To achiev...

Significance Viral infection activates IRF3 and NF-κB and induces the production of type I interferons and proinflammatory cytokines. In this study, we found that ubiquitin-specific protease 25 (USP25) was required for viral infection-triggered activation of IRF3 and NF-κB and subsequent production of type I IFNs and proinflammatory cytokines. Impo...

Interleukin-17 (IL-17) is cytokine with critical functions in multiple autoimmune diseases. However, its roles in type I diabetes and the underlying mechanisms remain to be fully elucidated. In the current study, we investigated the impact of IL-17 deficiency on streptozotocin (STZ) induced diabetes. Il-17(-/-) mice exhibited attenuated hyperglycem...

Within the interleukin-17 (IL-17) family of cytokines, IL-17A is known to be critical in the host defense against fungal infections; however, the function of the other IL-17 family members in anti-fungal immunity remains largely unknown. Here, we show that IL-17C expression was highly induced in kidney epithelial cells after fungal infection. Mice...

Obesity and metabolic disorders such as insulin resistance and type 2 diabetes have become a major threat to public health globally. The mechanisms that lead to insulin resistance in type 2 diabetes have not been well understood. In this study, we show that mice deficient in MAP kinase phosphatase 5 (MKP5) develop insulin resistance spontaneously a...

Plasmodium falciparum infection can result in severe disease which is associated with elevated inflammation and vital organ dysfunction; however malaria endemic residents gain protection from lethal outcomes and manifest only mild symptoms during infection. To characterize host responses associated with this more effective antimalarial response, we...

The interleukin-17 (IL-17) family of cytokines has emerged as a critical player in inflammatory diseases. Among them, IL-25 has been shown to be important in allergic inflammation and protection against parasitic infection. Here we have demonstrated that IL-17B, a poorly understood cytokine, functions to inhibit IL-25-driven inflammation. IL-17B an...

Epigenetic regulation of lineage-specific genes is important for the differentiation and function of T cells. Ten-eleven translocation (Tet) proteins catalyze 5-methylcytosine (5mC) conversion to 5-hydroxymethylcytosine (5hmC) to mediate DNA demethylation. However, the roles of Tet proteins in the immune response are unknown. Here, we characterized...

The inducible T cell costimulator (ICOS) is a potent promoter of organ inflammation in murine lupus. ICOS stimulates T follicular helper cell differentiation in lymphoid tissue, suggesting that it might drive autoimmunity by enhancing autoantibody production. Yet the pathogenic relevance of this mechanism remains unclear. It is also unknown whether...

The type I interferon system is essential for antiviral immune response and is a primary target of viral immune evasion strategies. Here, we show that virus infection induces the expression of MAPK phosphatase 5 (MKP5), a dual-specificity phosphatase (DUSP), in host cells. Mice deficient in MKP5 were resistant to H1N1 influenza infection, which is...

Members of the MAPK phosphatase (MKP) protein family play critical roles in immune responses through differential regulation of MAPK activation. In this study, we show that MKP7, also known as dual-specificity phosphatase 16, was required for CD4(+) T cell responses in vivo. Mkp7(-/-) CD4(+) T cells exhibited enhanced ERK and JNK activation, and pr...

Activating mutations of K-ras are one of the most common molecular alterations associated with lung cancer development. Several attempts to develop therapies directly targeting K-ras have been failed thus far, clearly state the need for new strategies to bring clinical benefits to patients displaying such a molecular profile. Using a conditional K-...

Humoral immunity, including Ab switching and somatic hypermutation, is critically regulated by CD4(+) T cells. T follicular helper (Tfh) cells have been recently shown to be a distinct T cell subset important in germinal center reactions. The transcriptional regulation of Tfh cell development and function has not been well understood. In this study...

Type I interferon system is essential for anti-viral immune response and is a primary target of viral immune evasion strategies. Influenza A viruses mainly utilize the non-structural protein 1 (NS1) to suppress host immune responses, especially the type I interferon system. Here, we showed influenza infection induces the expression of MAP kinase ph...

Last decade has seen quick developments in the understanding of a new type of T lymphocytes, Th17 cells. This information is benefiting the understanding and treatment of a variety of inflammatory diseases, as suggested by a recent paper in Immunity.

To study transcriptional pathways and develop targeted therapeutics for cGVHD, we studied the effects of emerging therapeutic agents targeting GCs. BCL6 is a master regulatory transcription factor, which facilitates GC development in a cooperative manner with emerging chromatin-associated factors, namely the EZH2 lysine methyltransferase and the BR...