Inflammasome components caspase-1 and adaptor protein apoptosis-associated speck-like proteins are important in resistance to Cryptosporidium parvum

Cryptosporidium spp. are opportunistic protozoan parasites that infect epithelial cells in the intestinal tract and cause a flu-like diarrheal illness. Innate immunity is key to limiting the expansion of parasitic stages early in infection. One mechanism in which it does this is through the generation of early cytokines, such as IL-18. The processing and secretion of mature IL-18 (and IL-1β) is mediated by caspase-1 which is activated within an inflammasome following the engagement of inflammasome-initiating sensors. We examined how the absence of caspase-1 and caspase-11, the adapter protein Asc, and other inflammasome components affects susceptibility to cryptosporidial infection by these and other key cytokines in the gut. We found that Casp-11^?/?Casp-1^?/? knockout mice have increased susceptibility to Cryptosporidium parvum infection as demonstrated by the 35-fold higher oocyst production (at peak infection) compared to wild-type mice. Susceptibility correlated with a lack of IL-18 in caspase-1 and caspase1/11 knockout mice, whereas IL-18 is significantly elevated in wildtype mice. IL-1β was not generated in any significant amount following infection nor was any increased susceptibility observed in IL-1β knockout mice. We also show that the adapter protein Asc is important to susceptibility, and that the caspase-1 canonical inflammasome signaling pathway is the dominant pathway in C. parvum resistance.     

The chromatin-remodeling protein BAF60/SWP73A regulates the plant immune receptor NLRs

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Genomic signatures of local adaptation in the Drosophila immune response

As environments and pathogen landscapes shift, host defenses must evolve to remain effective. Due to this selection pressure, among-species comparisons of genetic sequence data often find immune genes to be among the fastest evolving genes across the genome. The full extent and nature of these immune adaptations, however, remain largely unexplored. In a recent study, we analyzed patterns of selection within distinct components of the Drosophila melanogaster immune pathway. While we found evidence of positive selection within some immune processes, immune genes were not universally characterized by signatures of strong selection. On the contrary, we even found that some immune functions show greater than expected constraint. Overall these results highlight 2 major factors that appear to play an outsize role in determining a gene's evolutionary rate: the type of pathogen the gene targets and the gene's position within the immune network. These results join a growing body of literature that highlight the complexity of immune adaptation. Rather than there being uniformly strong selection across all immune genes, a combination of pathogen-specificity and host genetic constraints appear to play key roles in determining each immune gene's individual evolutionary trajectory.     

Distinctions in lymphocyte responses to IL-2 and IL-15 reflect differential ligand binding interactions with the IL-2Rbeta chain and suggest differential roles for the IL-2Ralpha and IL-15Ralpha subunits

More interleukin 15 (IL-15) than IL-2 was needed to generate comparable proliferative responses by phytohaemagglutinin (PHA) blasts and Tf-1beta cells expressing high affinity and intermediate affinity IL-2 receptor (IL-2R) complexes, respectively. The focus of these experiments was to determine the contribution of the shared IL-2 and IL-15 receptor components to these dose-response differences. Some of this difference can be attributed to the role of the IL-2Rbeta chain, in that HuMikbeta1, a monoclonal antibody recognizing the IL-2Rbeta chain, blocks 92.2+/-2.5% (mean+/-SE) of the IL-2 proliferative response by Tf-1beta cells but only inhibits 57.9+/-3.7% of the IL-15 response, indicating that IL-2 and IL-15 may physically utilize the IL-2Rbeta chain differently. Monoclonal antibody 341, which recognizes IL-2Rbeta but does not inhibit IL-2 binding to the IL-2Rbeta chain, blocks 35.4+/-2.3% of IL-15-stimulated proliferation of PHA blasts, while not affecting the IL-2-stimulated proliferation. Finally, although HuMikbeta1 does not inhibit IL-2 responses by PHA blasts bearing high affinity IL-2 receptors, HuMikbeta1 does block IL-15-stimulated proliferation by these same cells bearing high affinity IL-15 receptors (88.5+/-1.6% inhibition). This indicates that the role of IL-15Ralpha in the high affinity IL-15R complex is distinct from that of IL-2Ralpha in the high affinity IL-2R complex. Overall, these studies show that the physical interactions of the IL-2Rbetagammac complex with IL-2 are different than the interactions with IL-15.     

Exploration of a novel prognostic risk signatures and immune checkpoint molecules in endometrial carcinoma microenvironment

In this study, we devoted to investigate immune-related genes and tumor microenvironment (TME) in EC based on The Cancer Genome Atlas (TCGA) database. In total 799 up-regulated and 139 down-regulated immune-related and differentially expressed genes in EC were investigated for functional annotations and prognosis. By a conjoint Cox regression analysis, we built two risk models for OS and DFS, as well as the consistent nomograms. Immune-related pathways were revealed mostly enriched in the low-risk group. By further analyzing TME based on the risk signatures, the higher immune cell infiltration and activation, lower tumor purity and higher tumor mutational burden were found in low-risk group, which presented a better prognosis. Both the expression and immunophenoscore of immune checkpoints PD-1, CTLA4, PD-L1 and PD-L2 increased significantly in low-risk group. These findings may provide new ideas for novel biomarkers and immunotherapy targets in EC.     

Structural biology of the IL‐1 superfamily: Key cytokines in the regulation of immune and inflammatory responses

Interleukin‐1 superfamily of cytokines (IL‐1, IL‐18, IL‐33) play key roles in inflammation and regulating immunity. The mechanisms of agonism and antagonism in the IL‐1 superfamily have been pursued by structural biologists for nearly 20 years. New insights into these mechanisms were recently provided by the crystal structures of the ternary complexes of IL‐1β and its receptors. We will review here the structural biology related to receptor recognition by IL‐1 superfamily cytokines and the regulation of its cytokine activities by antagonists.     

The emerging role of soluble HLA-G in the control of chemotaxis

HLA-G is an immunosuppressive molecule, that impairs the function of different immune cell populations, both in physiological and pathological conditions.Here, we have analyzed data obtained by our group and others regarding sHLA-G concentration in plasma from patients with different diseases. Next, we have summarized novel data regarding the impairment of chemotaxis of different immune effector cells mediated by sHLA-G. Finally, we have discussed the impact of this function on the immune response during cancer, viral infection, autoimmunity, and on B cell differentiation in secondary lymphoid organs. In conclusion, we have delineated a role of sHLA-G in the control of chemotaxis of immune effector cells, that may be relevant to modulate immune responses in different settings.     

Prognostic value and immune cell infiltration of hypoxic phenotype‐related gene signatures in glioblastoma microenvironment

Glioblastoma (GBM) is a malignant intracranial tumour with the highest proportion and lethality. It is characterized by invasiveness and heterogeneity. However, the currently available therapies are not curative. As an essential environmental cue that maintains glioma stem cells, hypoxia is considered the cause of tumour resistance to chemotherapy and radiation. Growing evidence shows that immunotherapy focusing on the tumour microenvironment is an effective treatment for GBM; however, the current clinicopathological features cannot predict the response to immunotherapy and provide accurate guidance for immunotherapy. Based on the ESTIMATE algorithm, GBM cases of The Cancer Genome Atlas (TCGA) data set were classified into high‐ and low‐immune/stromal score groups, and a four‐gene tumour environment‐related model was constructed. This model exhibited good efficiency at forecasting short‐ and long‐term prognosis and could also act as an independent prognostic biomarker. Additionally, this model and four of its genes (CLECL5A, SERPING1, CHI3L1 and C1R) were found to be associated with immune cell infiltration, and further study demonstrated that these four genes might drive the hypoxic phenotype of perinecrotic GBM, which affects hypoxia‐induced glioma stemness. Therefore, these might be important candidates for immunotherapy of GBM and deserve further exploration.     

CXCR5 may be involved in the attraction of human metastatic neuroblastoma cells to the bone marrow

Introduction Up-regulation of some chemokine receptors on tumor cells is associated with increased metastatic potential. In this respect, limited information is available on chemokine receptor in human neuroblastoma (NB). Objects Purpose of the study was to identify chemokines/chemokine receptors involved in bone marrow (BM) localization of metastatic NB cells in view of the development of targeted therapeutic strategies. CD45⁻ metastatic NB cells were isolated from the BM of six patients by immunomagnetic bead manipulation. Some experiments were carried out using a panel of human neuroblastoma cell lines (GI-ME-N, GI-LI-N, LAN-5, HTLA-230, SH-SY-5Y and IMR-32). Immunophenotypic analyses were performed by flow cytometry. Cell migration assays were carried out using transwell systems. Calcium ion mobilization, chemokine receptor internalization and cell proliferation were investigated by flow cytometry. Results In all BM samples, CXCR5 was expressed by the majority of primary neuroblasts and mediated their chemotaxis in response to CXCL13. Primary metastatic NB cells from all BM samples expressed CXCR6, but were not attracted by soluble CXCL16. Studies performed with two CXCR6⁺ NB cell lines showed that the mechanism whereby neuroblasts did not migrate to CXCL16 was likely related to defective calcium ion mobilization. Conclusions CXCR5 is the first chemokine receptor so far identified able to attract in vitro primary metastatic NB cells. CXCR6 may be involved in retention of metastatic neuroblasts in the BM through interaction with CXCL16 expressing stromal cells in the absence of signal transduction.     

Cancer-associated fibroblasts: Vital suppressors of the immune response in the tumor microenvironment

Since the "seed and soil" hypothesis was proposed, the biological functions of the tumor microenvironment (TME), especially its stromal components, have received increasing attention. Cancer-associated fibroblasts (CAFs) are the major components of the stromal region, providing material support for tumor cell proliferation, migration, and invasion. Furthermore, CAFs are important mediators of suppressing immune responses by attracting the accumulation of immunosuppressive cells through cytokine/chemokine secretion. In this review, we summarized the major cytokines, chemokines and metabolites, including transforming growth factor-β (TGF-β), interleukin-6 (IL-6), C-X-C chemokine ligand (CXCL)12, C–C chemokine ligand (CCL) 2, prostaglandin E2 (PGE2), and other factors, by which CAFs suppress the immune systems in a variety of cancers. More importantly, we highlight potential therapeutic strategies to alleviate the immunosuppression produced by CAFs, thereby inhibiting tumor progression.     

聚肌胞免疫刺激下仔猪外周血单核细胞的基因表达分析

聚肌胞(Poly I:C)是一种天然双链RNA(Double strand RNA, dsRNA)的拟似物,能够模拟病毒感染后所形成的dsRNA及刺激机体产生抗病毒免疫反应。文章以抗病力存在差异的大蒲莲和长白仔猪为研究对象,分离外周血单核细胞(Peripheral blood mononuclear cell, PBMC),在20 μg/mL的Poly I:C的免疫刺激下体外培养24 h,对影响免疫应答过程中的7个细胞因子(IRF3、IL6、IL8、IL10、TNFα、IFNγ和IFNα)和3个模式识别受体(TLR3、TLR4和RIG1)利用实时荧光定量PCR检测Poly I:C免疫刺激组相对于对照组的基因表达变化倍数。结果表明：检测的大部分细胞因子和受体(6个)表达量变化倍数很大,其中3种白细胞介素IL6、IL8和IL10免疫刺激变化倍数最大,平均变化倍数分别为20.71、10.87和5.18倍。对不同个体和品种间的比较发现,不仅大蒲莲和长白两品种间(大蒲莲猪的变化倍数平均高于长白猪)而且同品种的3头全同胞仔猪间对Poly I:C免疫刺激的应答也存在较大的变化。文章利用Poly I:C体外模拟dsRNA对PBMC的感染,为下一步筛选仔猪对Poly I:C刺激的免疫应答基因及鉴定大蒲莲猪特殊的抗性基因奠定了基础。     

Effects of immunostimulants on ranched southern bluefin tuna Thunnus maccoyii: immune response, health and performance

Ranched southern bluefin tuna Thunnus maccoyii were fed baitfishes supplemented with vitamins (predominantly E and C) or vitamins and immunostimulants, nucleotides and β-glucans, over 12 weeks after transfer and monitored for enhancement in immune response, health and performance through their 19 week grow-out period. Fish from two different tows were sampled separately at three different sampling points: at transfer to grow-out pontoons, at 8 weeks post-transfer and at harvest, 19 weeks post-transfer. Lysozyme activity was enhanced during vitamin supplementation compared to control fish. Performance (i.e. survival, condition index and crude fat), health (i.e. blood plasma variables including pH, osmolality, cortisol, lactate and glucose) and alternative complement activity were not commonly improved through diet supplementation. There were some tow-specific improvements in performance through vitamin supplementation including survival, selected parasite prevalence and intensity, and alternative complement activity. Immunostimulant supplementation also showed a tow-specific improvement in plasma cortisol level. Tow-specific responses may suggest that life history, previous health condition and husbandry can affect the success of vitamin and immunostimulant enhancement of immune response, health and performance of ranched T. maccoyii.     

Dysregulation of the immune response in coronavirus disease 2019

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can trigger a cytokine storm in the pulmonary tissue by releasing various types of mediators, leading to acute respiratory distress syndrome (ARDS). Increased neutrophil-to-lymphocyte ratio, as well as CD4+ T lymphopenia, is reported in cases with novel coronavirus disease (COVID-19), meanwhile, lymphopenia is a significant finding in the majority of COVID-19 cases with a severe phenotype. Moreover, excessive activation of monocyte/macrophage and cytokine storms are associated with the severity of the disease and the related complications in SARS-CoV-2 infection. Understanding the immune response dysregulation in COVID-19 is essential to develop more effective diagnostic, therapeutic, and prophylactic strategies in this pandemic.     

An enhanced agent based model of the immune system response

We describe some recent enhancements introduced in C-ImmSim, a simulator of the immune system response that we have been developing for a number of years along with preliminary results produced by the simulation of the Highly Active Anti-Retroviral Therapy in HIV-1 infected patients.     

The N-terminal domain of CCL21 reconstitutes high affinity binding, G protein activation, and chemotactic activity, to the C-terminal domain of CCL19

CC chemokine receptor 7 (CCR7), which regulates the trafficking of leucocytes to the secondary lymphoid organs, has two endogenous chemokine ligands: CCL19 and CCL21. Although both ligands possess similar affinities for the receptor and similar abilities to promote G protein activation and chemotaxis, they share only 25% sequence identity. Here, we show that substituting N-terminal six amino acids of CCL21 (SDGGAQ) for the corresponding N-terminal domain of CCL19 (GTNDAE) results in a chimeric chemokine that exhibits high affinity binding and G protein activation of CCR7. These data demonstrate that despite dissimilar sequences, the amino terminal hexapeptide of these two chemokines is capable of performing similar roles resulting in receptor activation.     

The immunosuppressive and pro-tumor functions of CCL18 at the tumor microenvironment

Chemokines are essential mediators of immune cell trafficking. In a tumor microenvironment context, chemotactic cytokines are known to regulate the migration, positioning and interaction of different cell subsets with both anti- and pro-tumor functions. Additionally, chemokines have critical roles regarding non-immune cells, highlighting their importance in tumor growth and progression.CCL18 is a primate-specific chemokine produced by macrophages and dendritic cells. This chemokine presents both constitutive and inducible expression. It is mainly associated with a tolerogenic response and involved in maintaining homeostasis of the immune system under physiological conditions. Recently, CCL18 has been noticed as an important component of the complex chemokine system involved in the biology of tumors. This chemokine induces T regulatory cell differentiation and recruitment to the tumor milieu, with subsequent induction of a pro-tumor (M2-like) macrophage phenotype. CCL18 is also directly involved in cancer cell-invasion, migration, epithelial-to-mesenchymal transition and angiogenesis stimulation, pinpointing an important role in the promotion of cancer progression. Interestingly, this chemokine is highly expressed in tumor tissues, particularly at the invasive front of more advanced stages (e.g. colorectal cancer), and high levels are detected in the serum of patients, correlating with poor prognosis.Despite the promising role of CCL18 as a biomarker and/or therapeutic target to hamper disease progression, its pleiotropic functions in a context of cancer are still poorly explored. The scarce knowledge concerning the receptors for this chemokine, together with the insufficient insight on the downstream signaling pathways, have impaired the selection of this molecule as an immediate target for translational research.In this Review, we will discuss recent findings concerning the role of CCL18 in cancer, integrate recently disclosed molecular mechanisms and compile data from current clinical studies.     

Tumour angiogenesis normalized by myo-inositol trispyrophosphate alleviates hypoxia in the microenvironment and promotes antitumor immune response

Pathologic angiogenesis directly responds to tumour hypoxia and controls the molecular/cellular composition of the tumour microenvironment, increasing both immune tolerance and stromal cooperation with tumour growth. Myo-inositol-trispyrophosphate (ITPP) provides a means to achieve stable normalization of angiogenesis. ITPP increases intratumour oxygen tension (pO₂) and stabilizes vessel normalization through activation of endothelial Phosphatase-and-Tensin-homologue (PTEN). Here, we show that the tumour reduction due to the ITPP-induced modification of the tumour microenvironment by elevating pO₂ affects the phenotype and properties of the immune infiltrate. Our main observations are as follows: a relative change in the M1 and M2 macrophage-type proportions, increased proportions of NK and CD8⁺T cells, and a reduction in Tregs and Th2 cells. We also found, in vivo and in vitro, that the impaired access of PD1⁺NK cells to tumour cells is due to their adhesion to PD-L1⁺/PD-L2⁺ endothelial cells in hypoxia. ITPP treatment strongly reduced PD-L1/PD-L2 expression on CD45+/CD31+ cells, and PD1⁺ cells were more numerous in the tumour mass. CTLA-4⁺ cell numbers were stable, but level of expression decreased. Similarly, CD47⁺ cells and expression were reduced. Consequently, angiogenesis normalization induced by ITPP is the mean to revert immunosuppression into an antitumor immune response. This brings a key adjuvant effect to improve the efficacy of chemo/radio/immunotherapeutic strategies for cancer treatment.