The TYK2:p.Pro1104Ala (rs34536443) hypomorph variant has been associated with protection against numerous autoimmune disorders. Thus, its mechanism of action becomes of great interest. Here, consistent with the participation of activated immune cells in autoimmunity, we show that the variant regulates the levels of immune cells, and is associated particularly with higher levels of T and B lymphocytes, and especially the naïve (non-activated) compartment. Also, consistent with a protective function in autoimmunity, regulatory CD4+ T cell level was increased. Thus, this variant decreases the immune activation, protecting from autoimmunity. Our work identifies the cellular mechanism regulated by the TYK2:p.Pro1104Ala variant and supports TYK2 as a therapeutic target in autoimmunity.

Cancer is a complex and heterogeneous disease characterized by uncontrolled cell growth and proliferation. One hallmark of cancer cells is their ability to undergo metabolic reprogramming, which allows them to sustain their rapid growth and survival. This metabolic reprogramming creates an immunosuppressive microenvironment that facilitates tumour progression and evasion of the immune system. In this paper, we review the mechanisms underlying metabolic reprogramming in cancer cells and discuss how these metabolic alterations contribute to the establishment of an immunosuppressive microenvironment. We also explore potential therapeutic strategies targeting metabolic vulnerabilities in cancer cells to enhance immune-mediated anti-tumour responses.

Wnt5a plays an important role in the process of cell development and maturation and is closely related to various diseases, such as malignant tumors, metabolic disorders, fibrosis, growth and development. Recent studies have shown that Wnt5a expression regulation and signal transduction are closely related to inflammatory response. This paper comprehensively reviews the latest research progress on the relationship between Wnt5a and various inflammatory diseases, such as sepsis, asthma, chronic obstructive pulmonary disease, tuberculosis, rheumatoid arthritis, atherosclerosis, psoriasis vulgare, etc. The mechanism of Wnt5a protein in the pathogenesis of these diseases was elucidated, which provided a basis for the prevention and treatment of inflammatory diseases with Wnt5a as a possible target in the future.

Rheumatoid arthritis (RA) is a systemic autoimmune disease driven by highly active autoantibody producing B cells. These B cells can be supported within ectopic germinal centers found in afflicted joints. Fibroblast like synoviocytes (FLS) present in inflamed joints support B cell survival, activation and differentiation. CD27 + memory B cells and naïve B cells show very distinct reactions to activation, particularly by CD40 ligand (CD40L). We show that FLS dependent activation of human B cells is dependent on interleukin 6 (IL-6) and CD40L. FLS have been shown to activate naïve as well as memory B cells. If the activatory potential of FLS is different for naïve and memory B cells had not yet been investigated. Our results suggest that FLS-induced activation of B cells is dependent on IL-6 and CD40L. While FLS are capable of inducing differentiation, isotype switching and antibody production in memory B cells, FLS capability to activate naive B cells is significantly lower.

Objective: To evalute the expression of RAG and BCR gene rearrangement in mature peripheral B lymphocytes in Takayasu arteritis, reveal the possible mechanism of humoral immune response in Takayasu arteritis. Methods: Patients with Takayasu arteritis (10 cases) and healthy volunteers with age and sex matching (10cases, as control group) from Beijing Shijitan Hospital, Capital Medical University , and Peking Union Medical College Hospital from 2022 to 2023 were included in this study. The recombinant activating gene mRNA test uesd real-time quantitative PCR (RT-PCR) . Western blot was used to detect the expression levels of the RAG protein . The NGS gene sequencing technology was performed for the B cell receptor (BCR) gene sequencing. Results: The expression level of RAG1 mRNA and RAG2 mRNA in peripheral mature B lymphocytes in TA patients was significantly higher than that of normal controls（RAG1 5.56±1.71 vs. 1.94±0.86, P＜0.05; RAG2 5.26±1.59 vs. 1.65±0.64, P＜0.05）, respectively; The expression level of the RAG1 protein and the RAG2 protein in peripheral mature B lymphocytes in TA patients was significantly higher than that of normal controls（RAG1 4.33±1.58 vs. 1.52±0.59, P＜0.05; RAG2 4.67±1.88 vs. 1.59±0.56, P＜0.05）, respectively. The number of peripheral B lymphocyte BCR clonotypes in the group of patients with TA was significantly higher than in the normal control group（1574±317.7 vs. 801.3±202.1, P＜0.05）. The abundance of the BCR gene V region in TA patients was higher than that in the normal control group（31.185% vs. 13.449%）.The abundance of genes in the BCR V region was positively correlated with RAG1 and RAG2 (correlation coefficient r=1.00, P<0.05), respectively. Conclusion: High expression of the RAG gene in mature peripheral B lymphocytes may cause BCR secondary gene rearrangement in mature peripheral B lymphocytes in patients with Takayasu arteritis, suggesting that there is a possibility of secondary gene rearrangement in TA and providing important clues for the potential diagnostic indicator and therapeutic target of Takayasu arteritis, and further exploration and analysis is required for larger samples.

Pancreatic cancer (PC), a highly malignant tumor of the digestive system with poor therapeutic response and low survival rates. In recent years, immunotherapy have developed rapidly and achieved substantial results in many malignant neoplasms. However, responses to immunotherapy in PC are rare and its immunosuppressive and desmoplastic tumor microenvironment (TME) composes an important impediment to their efficacy in PC. Tumor-associated neutrophils (TANs) play a crucial role in the PC microenvironment, exerting a profound influence on PC immunotherapy through establishing a robust stromal shelter and restraining immune cells to assist PC cells in immune escape, which may subvert the current situation of immunotherapy for PC. The purpose of this review is to offer a thorough summary of the latest progress in comprehending the involvement of TANs in PC desmoplastic and immunosuppressive functions, as well as to emphasize the potential therapeutic consequences of focusing on TANs in the immunotherapy of this destructive ailment. Last but not least, we have provided an outlook for the future of TANs in PC immunotherapy.

Glioblastoma (GBM) is the most common and aggressive brain tumor with poor outcome. Immune checkpoint inhibitors (ICIs) have been tested in GBM and, despite disappointing results, the identification of a small subgroup of responders underlies the need to improve our understanding of the tumor microenvironment (TME) immunity. The aim of this study was to determine whether the expression of selected immune checkpoints on tissue-resident memory T cells (Trm) may predict patient outcome. We conducted a single cohort observational study. Tumor samples were collected from 45 patients with histologically confirmed, IDH wild type, GBM (WHO grade IV) and processed to obtain single cell suspensions. Using multiparametric flow cytometry and uni/multivariate analyses, patients were assessed for the correlation of Trm with overall survival (OS) and progression-free survival (PFS). High and low frequency of Trm expressing PD1 and TIM3 was found to be linked to clinical outcome. In fact, low frequency of Trm expressing PD1 or TIM3 or both markers defined subgroups as independent positive prognostic factors for patient survival. On multivariate analysis, low CD8+CD103+PD1+TIM3+ Trm and KPS ≥70 were confirmed to be the most predictive independent factors associated with longer OS (HR [95%CI]: 0.14 [0.04 - 0.52] p˂0.001, 0.39 [0.16 - 0.96] p=0.04, respectively). The CD8+CD103+ Trm subgroups also resulted age-linked predictors for survival in GBM.

Fucosylation plays a critical role in cell-to-cell interactions and disease progression. However, the effects of fucosylation on splenocytes and their interactions with T cells remain unclear. In this study, we aimed to explore the transcriptome profiles of splenocytes deficient in fucosyltransferase (FUT) 1, an enzyme that mediates fucosylation, and investigate their impact on the proliferation and differentiation of T cells. We analyzed and compared the transcriptomes of splenocytes isolated from Fut1 knockout (KO) mice and those from wild-type (WT) mice using RNA-seq. Additionally, we examined the effects of Fut1 KO splenocytes on CD4 T cell proliferation and differentiation, in comparison to WT splenocytes, and elucidated the mechanisms involved. The comparative analysis of transcriptomes between Fut1 KO and WT splenocytes revealed that thrombospondin (THBS)-1, among the genes related to immune response and inflammation, was the most highly downregulated gene in Fut1 KO splenocytes. The reduced expression of THBS1 was further confirmed using qRT-PCR and flow cytometry. In coculture experiments, Fut1 KO splenocytes promoted the proliferation of CD4 T cells and drove their differentiation towards Th1 and Th17 cells, compared to WT splenocytes. Moreover, the levels of IL-2, IFN-γ and IL-17 were increased, while IL-10 was decreased, in T cells cocultured with Fut1 KO splenocytes compared to those with WT splenocytes. These effects of Fut1 KO splenocytes on T cells were reversed when THBS1 was replenished. Taken together, our results demonstrate that splenocytes with Fut1 deficiency promote CD4 T cell proliferation and Th1/Th17 differentiation at least in part through THBS1 downregulation.

On the basis of the mechanisms of action and characteristics of immune effects, immunity is generally divided into innate and adaptive immunity. Adaptive immunity is associated with the response to non-self entities and is characterized by high specificity and memory. In contrast, innate immunity is believed to lack memory. However, an increasing number of studies have sought to challenge this traditional immunological dogma and have shown that innate immune cells respond to secondary stimulation more strongly and rapidly than to the primary triggers, thus providing evidence of the immune memory in innate immunity. Macrophages, which are among the most important innate immune cells, can also acquire memory that facilitates the mediation of recall responses. Macrophage memory is a relatively new concept that is revolutionizing our understanding of macrophage biology and immunological memory and could lead to a new class of vaccines and immunotherapies. In this review, we describe the characteristics and mechanisms of macrophage memory, as well as its key roles in various diseases.

Adoptive regulatory T cell (Treg) trasfer represents a potential therapeutic option to control immune responses in organ transplantation, graft vs host disease, and autoimmunity, including type 1 diabetes. Treg for adoptive therapy are traditionally sorted and expanded in vitro with high doses of IL-2, showing stability and suppressive capacity, but with some limitations in terms of long-term survival once infused in patients. Here, we tested a novel expansion protocol in which we added IL-7 (IL-7 method, IL-7M) to the traditional standard method (StM) using IL-2. We showed that naïve Treg express significant levels of CD127 and robustly respond to IL-7 by phosphorylating STAT-5. Naive Treg expanded with the IL-7M were highly enriched in CD45RA +CD62L +CD95 + showing a reduction in the final cell yield and suppressive function. Treg expanded with the IL-7M preserved telomere length and were more resistant to cytokine withdrawal and fas-mediated apoptosis. Overall our data indicate that it is possible to expand naïve Treg in the presence of IL-7 to generate a final Treg product enriched in poorly differentiated CD45RA + cells and with better resistance to stress and apoptosis, potentially improving the long-term survival of Treg in adoptive transfer protocols.

Objectives: Although various studies have been performed on the function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in RA, the results were conflicting. Here we were trying to clarify the role of PMN-MDSCs in the pathogenesis of RA and its specific mechanisms. Methods: We detected the frequencies and counts of PMN-MDSCs, TNF- + B cells, and Ki67 + B cells in spleens and inflamed joints of collagen-induced arthritis (CIA) mice using flow cytometry. The pathological role of PMN-MDSCs was examined by anti-Ly6G neutralizing antibodies against PMN-MDSCs or adoptive transfer of PMN-MDSCs. And the modulation of PMN-MDSCs on B cells was conducted by coculture assays, RNA-Seq, RT-qPCR, etc. The mechanism of BAFF regulating B cells was verified through Western Blot and flow cytometry. Results: PMN-MDSCs accumulated in the spleens and joints of CIA mice. PMN-MDSCs depletion could alleviate the arthritis severity, which was accompanied by decreased TNF- secretion and proliferation of B cells. And its adoptive transfer also facilitated disease progress. Furthermore, PMN-MDSCs from CIA mice had higher expression level of BAFF, which regulated TNF- expression, proliferation and apoptosis of B cells in vitro. What’s more, BAFF promoted phosphorylation of BTK/NF-B signaling pathway. And Ibrutinib (BTK inhibitor) could reverse the effect of BAFF on TNF- expression. Conclusions: Our study suggested that PMN-MDSCs enhanced disease severity of CIA and manipulated TNF- expression, proliferation and apoptosis of B cells via BAFF, furthermore, BAFF promoted TNF- expression through BTK/NF-B signaling pathway, which demonstrated a novel pathogenesis of PMN-MDSC in CIA.

Hepatocellular carcinoma has been a serious threat to human life and health, and there is an urgent need for new treatments to prolong the overall survival time of patients. The liver plays an immunomodulatory function due to its unique physiological structural characteristics; therefore, following surgical resection and radiotherapy, immunotherapeutic options have shown great potential in the treatment of hepatocellular carcinoma in recent years, and adoptive cellular immunotherapy is developing rapidly in the treatment of hepatocellular carcinoma. In this review we summarize the latest research on adoptive cell therapy for hepatocellular carcinoma, focusing on chimeric antigen receptor (CAR) T cells and T cell receptor-engineered (TCR) T cells, and then briefly discuss tumor infiltrating lymphocytes (TILs), natural killer (NK) cells and cytokine-induced killer cells (CIKs). The aim is to provide readers with a comprehensive understanding of the current status of HCC adoptive cellular immunotherapy and new therapeutic strategies being developed, in the hope of providing new ideas for the clinical management of hepatocellular carcinoma.

According to reports, gut microbiota and metabolites regulate intestinal immune microenvironment. In recent years, an increasing number of studies reported that bile acids (BAs) of intestinal flora origin affects T helper cells and Treg cells. Th17 cells play a pro-inflammatory role and Treg cells usually act an immunosuppressive role. In this review, we emphatically summarized the influence and corresponding mechanism of different configurations of the LCA and DCA on intestinal Th17 cells, Treg cells and intestinal immune microenvironment. The regulation of BAs receptors G protein-coupled bile acid receptor 1 (GPBAR1/TGR5) and farnesoid X receptor (FXR) on immune cells and intestinal environment are elaborated. Furthermore, the potential clinical applications above were also concluded in three aspects. These above will help researchers better understand the effects of gut flora on the intestinal immune microenvironment via BAs and contribute to the development of new targeted drugs.

NLR family pyrin domain containing 2 (NLRP2) is a novel member of the Nod-like receptor (NLR) family. However, our understanding of NLRP2 has long been ambiguous. NLRP2 may have a role in the innate immune response, but its specific  functions remain controversial. Although NLRP2 can initiate inflammasome and promote inflammation, it can also downregulate inflammatory signals. Additionally, NLRP2 has been reported to function in the reproductive system and shows high expression in the placenta. However, the exact role of NLRP2 in the reproductive system is unclear. Here, we highlight the most current progress on NLRP2 in inflammasome activation, effector function, and regulation of nuclear factor-κB. And we discuss functions of NLRP2 in inflammatory diseases, reproductive disorders, and the potential implication of NLRP2 in human diseases.