Immunology最新文献

The human innate immune system recognizes dsRNA as a pathogen-associated molecular pattern that induces a potent inflammatory response. The primary source of pathogenic dsRNA is cells infected with replicating viruses, but can also be released from uninfected necrotic cells. Here, we show that the dsRNA poly(I:C) challenge in human macrophages activates the p38 MAPK-MK2 signalling pathway and subsequently the phosphorylation of tristetraprolin (TTP/ZFP36). The latter is an mRNA decay-promoting protein that controls the stability of AU-rich mRNAs (AREs) that code for many inflammatory mediators. Hydroxychloroquine (HCQ), a common anti-malaria drug, is used to treat inflammatory and autoimmune disorders and, controversially, during acute COVID-19 disease. We found that HCQ reduced the dsRNA-dependent phosphorylation of p38 MAPK and its downstream kinase MK2. Subsequently, HCQ reduced the abundance and protein stability of the inactive (phosphorylated) form of TTP. HCQ reduced the levels and the mRNA stability of poly (I:C)-induced cytokines and inflammatory mRNAs like TNF, IL-6, COX-2, and IL-8 in THP-1 and primary blood monocytes. Our results demonstrate a new mechanism of the anti-inflammatory role of HCQ at post-transcriptional level (TTP phosphorylation) in a model of dsRNA activation, which usually occurs in viral infections or RNA release from necrotic tissue.

The clonal selection theory (CST) is the centrepiece of the current paradigm used to explain immune recognition and memory. Throughout the past decades, the original CST had been expanded and modified to explain new experimental evidences since its original publication by Burnet. This gave origin to new paradigms that govern experimental immunology nowadays, such as the associative recognition of antigen model and the stranger/danger signal model. However, these new theories also do not fully explain experimental findings such as natural autoimmune immunoglobulins, idiotypic networks, low and high dose tolerance, and dual-receptor T and B cells. To make sense of these empirical data, some authors have been trying to change the paradigm of immune cognition using a systemic approach, analogies with brain processing and concepts from second-order cybernetics. In the present paper, we review the CST and some of the theories/hypotheses derived from it, focusing on immune recognition. We point out their main weaknesses and highlight arguments made by their opponents and believers. We conclude that, until now, none of the proposed theories can fully explain the totality of immune phenomena and that a theory of everything is needed in immunology.

Tuberculosis (TB) is still an urgent global public health problem. Notably, mucosal-associated invariant T (MAIT) cells play an important role in early anti-TB immune response. Targeted control of them may be an effective method to improve vaccine efficacy and TB treatment. However, the biology and signal regulation mechanisms of MAIT cells in TB patients are still poorly understood. Previous studies have been limited by the lack of reagents to specifically identify MAIT cells. In addition, the use of alternative markers may subsume non-MAIT cell into MAIT cell populations. In this study, the human MR1 tetramer which can specifically identify MAIT cells was used to further explore the effect and mechanism of MAIT cells in anti-TB immune response. Our results showed that the tetramer⁺ MAIT cells in peripheral blood of TB patients were mainly CD8⁺ or CD4⁻CD8⁻ cells, and very few were CD4⁺ cells. After BCG infecting autologous antigen-presenting cells, MAIT cells in patients produced significantly higher levels of cytokines, lysis and proliferation compared with healthy controls. After suppression of mTORC1 by the mTORC1-specific inhibitor rapamycin, the immune response of MAIT cells in patients was significantly reduced. This study demonstrates that peripheral blood tetramer⁺ MAIT cells from TB patients have significant anti-TB immune effect, which is regulated by mTORC1. This could provide ideas and potential therapeutic targets for the development of novel anti-TB immunotherapy.

Thought of as a metastasis-associated gene, however, NME/NM23 nucleoside diphosphate kinase 4 (NME4) has rarely been described in the context of the tumour microenvironment. To understand the immunological implications of NME4 in oesophageal squamous cell carcinoma (ESCC), we used multiplex immunohistochemistry to analyse the clinicopathological and prognostic importance of NME4 expression. Then, after establishing a syngeneic tumour model with a C57BL/6 mouse strain that can recapitulate the tumour microenvironment of humans, we examined the immunological involvement of NME4 expression. To explore the underlying molecular mechanism, via quantitative proteomics and protein microarray screening, we investigated the potential signalling pathways involved. The clinicopathological and prognostic importance of NME4 expression is limited in ESCC patients. In vivo, single-cell RNA sequencing showed that NME4 strikingly prevented CD8+ T cells from infiltrating the tumour microenvironment in murine ESCC. Mechanistically, we mapped out the NFκB2-CCL5 axis that was negatively controlled by NME4 in the murine ESCC cell line AKR. Collectively, these data demonstrated that regulation of NFκB2-CCL5 axis by NME4 prevents CD8+ T cells infiltration in ESCC.

The commitment to specific T lymphocytes (T cell) lineages is governed by distinct transcription factors, whose expression is modulated through epigenetic mechanisms. Unravelling these epigenetic mechanisms that regulate T cell differentiation and function holds significant importance for understanding T cells. Menin, a multifunctional scaffolding protein, is implicated in various cellular processes, such as cell proliferation, cell cycle control, DNA repair and transcriptional regulation, primarily through epigenetic mechanisms. Existing research indicates Menin's impact on T cell differentiation and function, while a comprehensive and systematic review is currently lacking to consolidate these findings. In the current review, we have highlighted recent studies on the role of Menin in T cell differentiation and function, focusing mainly on its impact on the memory Th2 maintenance, Th17 differentiation and maintenance, CD4⁺ T cell senescence, and effector CD8⁺ T cell survival. Considering Menin's crucial function in maintaining effector T cell function, the potential of inhibiting Menin activity in mitigating inflammatory diseases associated with excessive T cell activation has also been emphasised.

Inflammatory bowel disease (IBD) and food allergy (FA) increase in tandem, but the potential impact of IBD on FA remains unclear. We sought to determine the role of IBD on FA. We first assessed the changes of FA-related risk factors in dextran sulphate sodium salt (DSS) induced colitis mice model. Then, we evaluated the role of IBD on FA in mice. FA responses were determined using a clinical allergy score, body temperature change, serum antibody levels, cytokines level and mouse mast cell protease 1 (MMCP-1) concentration. Accumulation of regulatory T cells was tested using flow cytometry. Intestinal changes were identified by histology, immunohistochemistry, gene expression and gut microbial community structure. In DSS-induced colitis mice model, we found the intestinal damage, colonic neutrophil infiltration, and downregulation of splenic Th2 cytokines and Tregs in mesenteric lymph nodes (MLN). Moreover, we also found that IBD can alleviate the FA symptoms and lead to the significant downregulation of Th2 cytokines, serum IgE and MMCP-1. However, IBD exacerbates intestinal injury and promotes the gene expression levels of IL-33 and IL-5 in the small intestine, damages the intestinal tissue structure and aggravates intestinal dysbiosis in FA. IBD functions as a double-edged sword in FA. From the perspective of clinical symptoms and humoral immune responses, IBD can reduce FA response by downregulating Th2 cytokines. But from the perspective of the intestinal immune system, IBD potentially disrupts intestinal tolerance to food antigens by damaging intestinal tissue structure and causing intestinal dysbiosis.

Among several quantitative trait loci involved in tuberculosis (TB) control in mice, one was mapped within the chromosome 17 segment occupied by the H2 complex and another within the chromosome 3 segment comprising the S100A8/9 genes, which encode neutrophil inflammatory factor S100A8/9. Previously, we developed a panel of H2-congenic mouse strains differing by small segments of the major histocompatibility complex Class II (MHC-II) region from TB-susceptible H2^j mice transferred onto the genetic background of the TB-resistant C57BL/6 (H2^b) strain. Susceptible B6.I-9.3 mice differ from B6 progenitors by the alleles of their only classical MHC-II H2-Aβ gene. The goals of the present study were to: (i) comprehensively characterise the differences in TB-related phenotypes between mice of the two strains and (ii) decipher interactions between the H2-Aβ and S100A8/9 genes. Here, we describe the dynamics of TB-related phenotypes differentiating B6.I-9.3 and B6 mice (colony forming units counts, histopathology, lung immune cell infiltration and cytokine profiles). We show that disproportionally diminished CD4⁺ T-cell population, an enlarged S100A8/9-positive neutrophil population and higher S100A8/9 serum levels in B6.I-9.3 mice collectively form the ‘susceptible’ phenotype before infection. An increase in IL-17 and a decrease in intrferon-gamma production by CD4⁺ T-cells in these mice provide a mechanistic explanation of this phenotype. Using F2 segregation analysis, we show that the number of S100A8/9-producing neutrophils in lungs and spleens and the proportion of Th17 CD4⁺ T-cells in lungs are significantly lower in the presence of the MHC-II dominant ‘resistant’ b allele compared to the recessive ‘susceptible’ j/j genotype. This provides direct genetic evidence that MHC-II-regulated CD4⁺ T-cell landscapes determine neutrophil abundance before infection, an important pathogenic factor in TB immunity.

The adverse effects observed in some cancer patients treated with erythropoiesis-stimulating agents such as erythropoietin (EPO) might be due to the latter's well-known immunosuppressive functions. Here, we used a mouse model of syngeneic triple-negative breast cancer to explore EPO's immunomodulatory role in a tumour setting. Our results showed that EPO treatment promotes tumour growth, exacerbates the ‘immune desert’, and results in a ‘cold tumour’. EPO treatment changed the immune cell distribution in peripheral blood, secondary lymphoid organs, and the tumour microenvironment (TME). Our in-depth analysis showed that EPO mainly impacts CD4 T cells by accelerating their activation in the spleen and thus their subsequent exhaustion in the TME. This process is accompanied by a general elevation of CD39 expression by several immune cells (notably CD4 T cells in the tumour and spleen), which promotes an immunosuppressive TME. Lastly, we identified a highly immunosuppressive CD39⁺ regulatory T cell population (ICOS⁺, CTLA4⁺, Ki67⁺) as a potential biomarker of the risk of EPO-induced tumour progression. EPO displays pleiotropic immunosuppressive functions and enhances mammary tumour progression in mice.

Targeting immune receptors on T cells is a common strategy to treat cancer and autoimmunity. Frequently, this is accomplished through monoclonal antibodies targeting the ligand binding sites of stimulatory or inhibitory co-receptors. Blocking ligand binding prevents downstream signalling and modulates specific T cell functions. Since 1985, the FDA has approved over 100 monoclonal antibodies against immune receptors. This therapeutic approach significantly improved the care of patients with numerous immune-related conditions; however, many patients are unresponsive, and some develop immune-related adverse events. One reason for that is the lack of consideration for the localization of these receptors on the cell surface of the immune cells in the context of the immune synapse. In addition to blocking ligand binding, changing the location of these receptors on the cell surface within the different compartments of the immunological synapse could serve as an alternative, efficient, and safer approach to treating these patients. This review discusses the potential therapeutic advantages of altering proteins' localization within the immune synapse and summarizes published work in this field. It also discusses the novel use of bispecific antibodies to induce the clustering of receptors on the cell surface. It presents the rationale for developing novel antibodies, targeting the organization of signalling receptor complexes on the cell surface. This approach offers an innovative and emerging technology to treat cancer patients resistant to current immunotherapies.