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Background/aim: Innate-like T lymphocytes are a recently defined group of T cells comprising mainly mucosa-associated invariant T (MAIT) cells. The relationship between MAIT cells and childhood asthma is controversial. In this study, we aimed to determine the role of MAIT cells in patients with allergic asthma (AA) and nonallergic asthma (NAA). This is the first study to compare the ratios of these cells in patients with AA and NAA. Materials and methods: The study included children aged 6-18 years with AA (n = 41) or NAA (n = 30) and healthy control subjects (n = 36). The control group consisted of children who presented to the outpatient clinic without chronic disease, malnutrition, or acute or chronic infection. The proportions of MAIT, TH17, MAIT-17, and Th17-17 cells were investigated by flow cytometry and compared among the AA, NAA, and control groups. Results: When the AA and NAA patient groups were compared, the mean MAIT cell ratio was significantly lower in NAA patients (median: 0.45, p < 0.05). MAIT cell ratios were also substantially lower in NAA patients compared to the control group (mean: 0.504, p < 0.05). TH17, MAIT-17, and TH17-17 cell values were not statistically significant among the groups. Conclusion: Our study found that MAIT cell ratios were lower in the NAA patient group compared to the control group and AA patients. It has been predicted that MAIT cell depletion may have a role in the development of NAA. Our study is the first on this subject in the literature and further studies are needed. [ABSTRACT FROM AUTHOR]

• Triterpenoid of Hibiscus tiliaceus leaf fraction have immunopotentiator effect on TLR-2, TLR-4, NLRP-3, Dectin-1 based on binding affinity score. • Molecular dynamic simulation of triterpenoid-receptor complex is stable on water solvent. • The amino acid residues of triterpenoid similar with Quillaic acid as a references standard. Some plants are a source of vaccine adjuvants due to their rich triterpenoid saponin content. Hibiscus tiliaceus is a medicinal plant that is high in terpenoid-saponin. However, their potency as immunostimulants has not been well studied. The present in silico study evaluated the immunopotentiating activity of terpenoids extracted from H. tiliaceus leaf fraction as a candidate for vaccine adjuvants. Terpenoids were extracted from the leaf powder of H. tiliaceus and fractionated using gas chromatography-mass spectrometry (GC–MS). The PASS online web-based tool was utilized to screen the immunostimulatory potential of the terpenoids, and their toxicity prediction was performed using ADMETlab, pkCSM, and AdmetSAR web-based tools. Meanwhile, Auto Dock Vina 1.2.3 was used to molecularly dock terpenoids against pattern recognition receptors (PRRs), and perform molecular dynamic analysis. Nineteen terpenoid compounds were identified from the H. tiliaceus fraction, and triterpenoid groups demonstrated a high immunostimulatory potential based on a probability to be active (pa) with a value of >0.07. The triterpenoid group also included ß-amyrin (BAM), glitinol (GLU), and germanicol (GER), which demonstrated a high binding affinity against PRRs and toxicity prediction. Triterpenoid amino acid residues bind similarly to quillaic acid, the standard reference. The molecular dynamics simulation of the ligand-receptor complex indicated that it is stable in the water solvent. The findings of the study revealed that the triterpenoids from H. tiliaceus leaf fraction are a potential candidate for vaccine adjuvants, but the toxicity must be considered. [ABSTRACT FROM AUTHOR]

The successful development of germinal centers (GC) relies heavily on innate mechanisms to amplify the initial inflammatory cascade. In addition to their role in antigen presentation, innate cells are essential for the redirection of circulating lymphocytes toward the draining lymph node (dLN) to maximize antigen surveillance. Sphingosine-1-Phosphate (S1P) and its receptors (S1PR1-5) affect various aspects of immunity; however, the role of S1PR4 in regulating an immune response is not well understood. Here we use a footpad model of localized TH1 inflammation to carefully monitor changes in leukocyte populations within the blood, the immunized tissue, and the dLN. Within hours of immunization, neutrophils failed to adequately mobilize and infiltrate into the footpad tissue of S1PR4-/- mice, thereby diminishing the local vascular changes thought to be necessary for redirecting circulating cells toward the inflamed region. Neutrophil depletion with anti-Ly6G antibodies significantly reduced early tissue edema as well as the redirection and initial accumulation of naïve lymphocytes in dLN of WT mice, while the effects were less prominent or absent in S1PR4-/- dLN. Adoptive transfer experiments further demonstrated that the lymphocyte homing deficiencies in vivo were not intrinsic to the donor S1PR4-/- lymphocytes, but were instead attributed to differences within the S1PR4-deficient host. Reduced cell recruitment in S1PR4-/- mice would seed the dLN with fewer antigen-respondent lymphocytes and indeed, dLN hypertrophy at the peak of the immune response was severely diminished, with attenuated GC and activation pathways in these mice. Histological examination of the S1PR4-/- dLN also revealed an underdeveloped vascular network with reduced expression of the leukocyte tethering ligand, PNAd, within high endothelial venule regions, suggesting inadequate growth of the dLN meant to support a robust GC response. Thus, our study reveals that S1PR4 may link early immune modulation by neutrophils to the initial recruitment of circulating lymphocytes and downstream expansion and maturation of the dLN, thereby contributing to optimal GC development during an adaptive response. [ABSTRACT FROM AUTHOR]

The successful development of germinal centers (GC) relies heavily on innate mechanisms to amplify the initial inflammatory cascade. In addition to their role in antigen presentation, innate cells are essential for the redirection of circulating lymphocytes toward the draining lymph node (dLN) to maximize antigen surveillance. Sphingosine-1-Phosphate (S1P) and its receptors (S1PR1-5) affect various aspects of immunity; however, the role of S1PR4 in regulating an immune response is not well understood. Here we use a footpad model of localized TH1 inflammation to carefully monitor changes in leukocyte populations within the blood, the immunized tissue, and the dLN. Within hours of immunization, neutrophils failed to adequately mobilize and infiltrate into the footpad tissue of S1PR4-/- mice, thereby diminishing the local vascular changes thought to be necessary for redirecting circulating cells toward the inflamed region. Neutrophil depletion with anti-Ly6G antibodies significantly reduced early tissue edema as well as the redirection and initial accumulation of naïve lymphocytes in dLN of WT mice, while the effects were less prominent or absent in S1PR4-/- dLN. Adoptive transfer experiments further demonstrated that the lymphocyte homing deficiencies in vivo were not intrinsic to the donor S1PR4-/- lymphocytes, but were instead attributed to differences within the S1PR4-deficient host. Reduced cell recruitment in S1PR4-/- mice would seed the dLN with fewer antigen-respondent lymphocytes and indeed, dLN hypertrophy at the peak of the immune response was severely diminished, with attenuated GC and activation pathways in these mice. Histological examination of the S1PR4-/- dLN also revealed an underdeveloped vascular network with reduced expression of the leukocyte tethering ligand, PNAd, within high endothelial venule regions, suggesting inadequate growth of the dLN meant to support a robust GC response. Thus, our study reveals that S1PR4 may link early immune modulation by neutrophils to the initial recruitment of circulating lymphocytes and downstream expansion and maturation of the dLN, thereby contributing to optimal GC development during an adaptive response.

Knowledge of aging biology needs to be expanded due to the continuously growing number of elderly people worldwide. Aging induces changes that affect all systems of the body. The risk of cardiovascular disease and cancer increases with age. In particular, the age-induced adaptation of the immune system causes a greater susceptibility to infections and contributes to the inability to control pathogen growth and immune-mediated tissue damage. Since the impact of aging on immune function, is still to be fully elucidated, this review addresses some of the recent understanding of age-related changes affecting key components of immunity. The emphasis is on immunosenescence and inflammaging that are impacted by common infectious diseases that are characterized by a high mortality, and includes COVID-19, HIV and tuberculosis. [ABSTRACT FROM AUTHOR]

Thalassophryne nattereri toadfish (niquim) envenomation, common in the hands and feet of bathers and fishermen in the north and northeast regions of Brazil, is characterized by local symptoms such as immediate edema and intense pain. These symptoms progress to necrosis that lasts for an extended period of time, with delayed healing. Wound healing is a complex process characterized by the interdependent role of keratinocytes, fibroblasts, and endothelial and innate cells such as neutrophils and macrophages. Macrophages and neutrophils are actively recruited to clear debris during the inflammatory phase of wound repair, promoting the production of pro-inflammatory mediators, and in the late stage, macrophages promote tissue repair. Our hypothesis is that injury caused by T. nattereri venom (VTn) leads to senescent wounds. In this study, we provide valuable information about the mechanism(s) behind the dysregulated inflammation in wound healing induced by VTn. We demonstrate in mouse paws injected with the venom the installation of γH2AX/p16Ink4a-dependent senescence with persistent neutrophilic inflammation in the proliferation and remodeling phases. VTn induced an imbalance of M1/M2 macrophages by maintaining a high number of TNF-α-producing M1 macrophages in the wound but without the ability to eliminate the persistent neutrophils. Chronic neutrophilic inflammation and senescence were mediated by cytokines such as IL-1α and IL-1β in a caspase-1- and caspase-11-dependent manner. In addition, previous blocking with anti-IL-1α and anti-IL-β neutralizing antibodies and caspase-1 (Ac YVAD-CMK) and caspase-11 (Wedelolactone) inhibitors was essential to control the pro-inflammatory activity of M1 macrophages induced by VTn injection, skewing towards an anti-inflammatory state, and was sufficient to block neutrophil recruitment and senescence. [ABSTRACT FROM AUTHOR]

Knowledge of aging biology needs to be expanded due to the continuously growing number of elderly people worldwide. Aging induces changes that affect all systems of the body. The risk of cardiovascular disease and cancer increases with age. In particular, the age-induced adaptation of the immune system causes a greater susceptibility to infections and contributes to the inability to control pathogen growth and immune-mediated tissue damage. Since the impact of aging on immune function, is still to be fully elucidated, this review addresses some of the recent understanding of age-related changes affecting key components of immunity. The emphasis is on immunosenescence and inflammaging that are impacted by common infectious diseases that are characterized by a high mortality, and includes COVID-19, HIV and tuberculosis.

Introduction: Current human papillomavirus (HPV) vaccines consist of viruslike particles (VLPs) which are based on the L1 protein, but they are produced by different expression systems and use different adjuvants. We performed indepth immunophenotyping of multiple innate and adaptive immune cells after vaccination with bivalent versus nonavalent HPV vaccines. Method: Twenty pre-menopausal HPV-seronegative women were enrolled and randomized to receive three-doses of either the bivalent or the nonavalent HPV vaccine. Blood samples were collected at multiple time points from baseline up to 7 months after first vaccination. Four extensive EuroFlow flow cytometry antibody panels were used to monitor various immune cell subsets. Additionally, HPV-specific memory B- and T cells were determined by ELISPOT and HPVspecific antibody levels were measured by a VLP-based multiplex immunoassay. Results: In both cohorts, the numbers of plasma cells expanded in the first week after both primary and tertiary vaccination. HPV16 and HPV18-specific antibody levels and memory B and T-cell responses were higher in the bivalent than in the nonavalent vaccinees one month post third vaccination. For HPV31 and HPV45-specific antibody levels this pattern was reversed. Monocytes showed an expansion one day after vaccination in both cohorts but were significantly higher in the bivalent vaccine cohort. Large heterogeneity in responses of the other cell subsets was observed between donors. Conclusion: This pilot study showed a consistent response of monocytes and plasma cells after vaccination and a considerable variation in other circulating immune cells in both types of HPV vaccines between donors. [ABSTRACT FROM AUTHOR]

IntroductionCurrent human papillomavirus (HPV) vaccines consist of virus-like particles (VLPs) which are based on the L1 protein, but they are produced by different expression systems and use different adjuvants. We performed in-depth immunophenotyping of multiple innate and adaptive immune cells after vaccination with bivalent versus nonavalent HPV vaccines.MethodTwenty pre-menopausal HPV-seronegative women were enrolled and randomized to receive three-doses of either the bivalent or the nonavalent HPV vaccine. Blood samples were collected at multiple time points from baseline up to 7 months after first vaccination. Four extensive EuroFlow flow cytometry antibody panels were used to monitor various immune cell subsets. Additionally, HPV-specific memory B- and T cells were determined by ELISPOT and HPV-specific antibody levels were measured by a VLP-based multiplex immunoassay.ResultsIn both cohorts, the numbers of plasma cells expanded in the first week after both primary and tertiary vaccination. HPV16 and HPV18-specific antibody levels and memory B and T-cell responses were higher in the bivalent than in the nonavalent vaccinees one month post third vaccination. For HPV31 and HPV45-specific antibody levels this pattern was reversed. Monocytes showed an expansion one day after vaccination in both cohorts but were significantly higher in the bivalent vaccine cohort. Large heterogeneity in responses of the other cell subsets was observed between donors.ConclusionThis pilot study showed a consistent response of monocytes and plasma cells after vaccination and a considerable variation in other circulating immune cells in both types of HPV vaccines between donors.

Pediatric SARS‐CoV‐2 infection is often mild or asymptomatic and the immune responses of children are understudied compared to adults. Here, we present and evaluate the performance of a two‐panel (16‐ and 17 parameter) flow cytometry‐based approach for immune phenotypic analysis of cryopreserved PBMC samples from children after SARS‐CoV‐2 infection. The panels were optimized based on previous SARS‐CoV‐2 related studies for the pediatric immune system. PBMC samples from seven SARS‐CoV‐2 seropositive children from early 2020 and five age‐matched healthy controls were stained for analysis of T‐cells (panel T), B and innate immune cells (panel B). Performance of the panels was evaluated in two parallel approaches, namely classical manual gating of known subpopulations and unbiased clustering using the R‐based algorithm PhenoGraph. Using manual gating we clearly identified 14 predefined subpopulations of interest for panel T and 19 populations in panel B in low‐volume pediatric samples. PhenoGraph found 18 clusters within the T‐cell panel and 21 clusters within the innate and B‐cell panel that could be unmistakably annotated. Combining the data of the two panels and analysis approaches, we found expected differentially abundant clusters in SARS‐CoV‐2 seropositive children compared to healthy controls, underscoring the value of these two panels for the analysis of immune response to SARS‐CoV‐2. We established a two‐panel flow cytometry approach that can be used with limited amounts of cryopreserved pediatric samples. Our workflow allowed for a rapid, comprehensive, and robust pediatric immune phenotyping with comparable performance in manual gating and unbiased clustering. These panels may be adapted for large multi‐center cohort studies to investigate the pediatric immune response to emerging virus variants in the ongoing and future pandemics. [ABSTRACT FROM AUTHOR]

Intravenous immunoglobulin (IVIG) is one of the widely used immunotherapeutic molecules in the therapy of autoimmune and inflammatory diseases. Previous reports demonstrate that one of the anti-inflammatory actions of IVIG implicates suppression of macrophage activation and release of their inflammatory mediators. However, macrophages are highly plastic and depending on the microenvironmental signals, macrophages can be polarized into pro-inflammatory classic (M1) or anti-inflammatory alternative (M2) type. This plasticity of macrophages raised additional questions on the role of IVIG towards macrophage polarization. In the present report, we show that IVIG affects the polarization of both classically and alternatively activated macrophages and this process is F(ab’)2-independent. Our data thus indicate the lack of reciprocal regulation of inflammatory and non-inflammatory macrophages by IVIG.

Infection with Mycobacterium tuberculosis causes >1.5 million deaths worldwide annually. Innate immune cells are the first to encounter M. tuberculosis, and their response dictates the course of infection. Dendritic cells (DCs) activate the adaptive response and determine its characteristics. Macrophages are responsible both for exerting cell-intrinsic antimicrobial control and for initiating and maintaining inflammation. The inflammatory response to M. tuberculosis infection is a double-edged sword. While cytokines such as TNF-α and IL-1 are important for protection, either excessive or insufficient cytokine production results in progressive disease. Furthermore, neutrophils—cells normally associated with control of bacterial infection—are emerging as key drivers of a hyperinflammatory response that results in host mortality. The roles of other innate cells, including natural killer cells and innate-like T cells, remain enigmatic. Understanding the nuances of both cell-intrinsic control of infection and regulation of inflammation will be crucial for the successful development of host-targeted therapeutics and vaccines. [ABSTRACT FROM AUTHOR]

Spondyloarthritis (SpA) is a chronic inflammatory rheumatism characterized by inflammation of sacroiliac joints, peripheral joints, and spine. The Assessment of SpondyloArthritis Society describes three disease forms: axial (axSpA), peripheral, and enthesitic SpA. Each may be associated with extra-articular manifestations: psoriasis, inflammatory bowel disease, and acute anterior uveitis. Genome-wide association studies performed in axSpA and psoriatic arthritis (PsA) have shown a shared genetic background, especially the interleukin 23 (IL-23)/IL-17 pathway, which suggests pathophysiological similarities. The convincing positive results of clinical trials assessing the effect of secukinumab and ixekizumab (anti-IL-17A monoclonal antibodies) in axSpA and PsA have reinforced the speculated crucial role of IL-17 in SpA. Nevertheless, and obviously unexpectedly, the differential efficacy of anti-IL-23–targeted treatments between axSpA (failure) and PsA (success) has profoundly disrupted our presumed knowledge of disease pathogeny. The cells able to secrete IL-17, their dependence on IL-23, and their respective role according to the clinical form of the disease is at the heart of the current debate to potentially explain these observed differences in efficacy of IL-23/IL-17–targeted therapy. In fact, IL-17 secretion is usually mainly related to T helper 17 lymphocytes. Nevertheless, several innate immune cells express IL-23 receptor and can produce IL-17. To what extent these alternative cell populations can produce IL-17 independent of IL-23 and their respective involvement in axSpA and PsA are the crucial scientific questions in SpA. From this viewpoint, this is a nice example of a reverse path from bedside to bench, in which the results of therapeutic trials allow for reflecting more in depth on the pathophysiology of a disease. Here we provide an overview of each innate immunity-producing IL-17 cell subset and their respective role in disease pathogeny at the current level of our knowledge.

Downstream of kinase (Dok) 3 is a member of the Dok family of adaptor proteins known to regulate signaling pathways downstream of various immunoreceptors. As Dok-3 lacks intrinsic catalytic activity, it functions primarily as a molecular scaffold to facilitate the nucleation of protein complexes in a regulated manner and hence, achieve specificity in directing signaling cascades. Since its discovery, considerable progress has been made toward defining the role of Dok-3 in limiting B cell-receptor signaling. Nonetheless, Dok-3 has since been implicated in the signaling of Toll-like and C-type lectin receptors. Emerging data further demonstrate that Dok-3 can act both as an activator and inhibitor, in lymphoid and non-lymphoid cell types, suggesting Dok-3 involvement in a plethora of signal transduction pathways. In this review, we will focus on the structure and expression profile of Dok-3 and highlight its role during signal transduction in B cells, innate cells as well as in bone and lung tissues.

Spondyloarthritis (SpA) is a chronic inflammatory rheumatism characterized by inflammation of sacroiliac joints, peripheral joints, and spine. The Assessment of SpondyloArthritis Society describes three disease forms: axial (axSpA), peripheral, and enthesitic SpA. Each may be associated with extra-articular manifestations: psoriasis, inflammatory bowel disease, and acute anterior uveitis. Genome-wide association studies performed in axSpA and psoriatic arthritis (PsA) have shown a shared genetic background, especially the interleukin 23 (IL-23)/IL-17 pathway, which suggests pathophysiological similarities. The convincing positive results of clinical trials assessing the effect of secukinumab and ixekizumab (anti-IL-17A monoclonal antibodies) in axSpA and PsA have reinforced the speculated crucial role of IL-17 in SpA. Nevertheless, and obviously unexpectedly, the differential efficacy of anti-IL-23–targeted treatments between axSpA (failure) and PsA (success) has profoundly disrupted our presumed knowledge of disease pathogeny. The cells able to secrete IL-17, their dependence on IL-23, and their respective role according to the clinical form of the disease is at the heart of the current debate to potentially explain these observed differences in efficacy of IL-23/IL-17–targeted therapy. In fact, IL-17 secretion is usually mainly related to T helper 17 lymphocytes. Nevertheless, several innate immune cells express IL-23 receptor and can produce IL-17. To what extent these alternative cell populations can produce IL-17 independent of IL-23 and their respective involvement in axSpA and PsA are the crucial scientific questions in SpA. From this viewpoint, this is a nice example of a reverse path from bedside to bench, in which the results of therapeutic trials allow for reflecting more in depth on the pathophysiology of a disease. Here we provide an overview of each innate immunity-producing IL-17 cell subset and their respective role in disease pathogeny at the current level of our knowledge. [ABSTRACT FROM AUTHOR]

Conventional αβ CAR-T cell-based approaches have revolutionized the field of cancer immunotherapy, but hurdles remain, especially for solid tumors. Novel strategies in conjunction with alternative cell types are therefore required for effective CAR-based therapies. In this respect, innate and innate-like cells with unique immune properties, such as natural killer (NK) cells, NKT cells, γδ T cells, and macrophages, are promising alternatives to αβ CAR-T adoptive therapy. We review the applicability of these cells in the context of CAR therapy, focusing on therapies under development, the advantages of these approaches relative to conventional CAR-T cells, and their potential in allogeneic therapies. We also discuss the inherent limitations of these cell types and approaches, and outline numerous strategies to overcome the associated obstacles. Innate and innate-like cells exert potent antitumor effects and present several advantages as platforms for CAR development, especially for the treatment of solid tumors. Innate and innate-like cells offer new opportunities for allogeneic 'off-the-shelf' innate and innate-like CAR-based therapy in the treatment of cancer. Innate and innate-like cells show solid potential as vehicles for CARs, but the reduced survival and durability of these cells may limit their potential in the clinic. Arming innate and innate-like cells with refined next-generation CAR designs and novel gene-editing approaches can help to eliminate the associated roadblocks and permit fine-tuning of antitumor immunity. [ABSTRACT FROM AUTHOR]

Downstream of kinase (Dok) 3 is a member of the Dok family of adaptor proteins known to regulate signaling pathways downstream of various immunoreceptors. As Dok-3 lacks intrinsic catalytic activity, it functions primarily as a molecular scaffold to facilitate the nucleation of protein complexes in a regulated manner and hence, achieve specificity in directing signaling cascades. Since its discovery, considerable progress has been made toward defining the role of Dok-3 in limiting B cell-receptor signaling. Nonetheless, Dok-3 has since been implicated in the signaling of Toll-like and C-type lectin receptors. Emerging data further demonstrate that Dok-3 can act both as an activator and inhibitor, in lymphoid and non-lymphoid cell types, suggesting Dok-3 involvement in a plethora of signal transduction pathways. In this review, we will focus on the structure and expression profile of Dok-3 and highlight its role during signal transduction in B cells, innate cells as well as in bone and lung tissues. [ABSTRACT FROM AUTHOR]

Urinary tract infection (UTI) is the most common type of bacterial infection in humans. Fifty percent of all women will experience at least one UTI in their lifetime, with uropathogenic Escherichia coli (UPEC) accounting for 80% of reported cases. UTI evokes a complex, well-timed immune response that is crucial for bacterial clearance. The majority of immune cells participating in the immune response are absent from the healthy bladder, and the mechanisms used to recruit them upon UTI are not fully understood. Here, we show that immediately after UPEC infection, bladder epithelial cells secrete stromal cell-derived factor 1 (SDF-1), initiating immune cell accumulation at the site of infection. SDF-1 blockade significantly reduced immune cell migration to the infected bladder, resulting in severe exacerbation of infection. We also show that FimH, the adhesin of type 1 fimbria, one of UPEC’s virulence factors, is directly involved in the secretion of SDF-1 upon UTI.

Abstract The expression of elements of the cholinergic system has been demonstrated in non-neuronal cells, such as immune cells, where acetylcholine modulates innate and adaptive responses. However, the study of the non-neuronal cholinergic system has focused on lymphocyte cholinergic mechanisms, with less attention to its role of innate cells. Considering this background, the aims of this review are 1) to review information regarding the cholinergic components of innate immune system cells; 2) to discuss the effect of cholinergic stimuli on cell functions; 3) and to describe the importance of cholinergic stimuli on host immunocompetence, in order to set the base for the design of intervention strategies in the biomedical field. Highlights • Cholinergic system and innate cells • Neuroimmunomodulation by cholinergic agents • Innate immune cells and neuroimmunomodulation [ABSTRACT FROM AUTHOR]

Abstract Introduction Innate immunity represents the first step of activation of the immune system and dictates the quality of adaptive immune responses. Studies have reported links between systemic inflammatory or innate immune markers and prognosis in patients with lung cancer. To our knowledge, the prospective and concomitant study of these systemic markers has never been performed. Methods Advanced treatment-naive non–small cell lung cancer (NSCLC) patients eligible for first-line platinum-based chemotherapy were prospectively included from December 2012 to July 2015 (N = 148). Blood samples of patients were collected before the first cycle for fresh NK cell phenotyping. Peripheral blood mononuclear cells were cryopreserved for natural cytotoxicity receptor (NCR) genotyping as well as sera for NCR's ligand quantification. Data on leukocytes, neutrophils and monocyte counts and lactate dehydrogenase (LDH) levels were extracted from electronic medical records. Results Among all studied markers, monocytosis, neutrophilia, leucocytosis, high LDH and sBAG6 levels and reduced levels of NCR3 transcripts were associated with poor overall survival (OS) in univariate analysis. The levels of NCR3 transcripts was linked to age, number of metastatic sites, monocyte counts, LDH and sBAG6 levels. Neutrophilia was associated to high sBAG6 levels. NCR3 was the unique innate immune parameter that remained as an independent factor associated with both OS (P = 0.003) and progression-free survival (P = 0.009) in the multivariate analysis. Conclusion This study brought evidence that these biomarkers are entangled; parameters associated with an inflammatory process were related to reduced levels of NCR3 transcripts. Finally, the level of NCR3 transcripts was independently associated with outcomes in treatment-naive patients with advanced NSCLC. Highlights • Natural killer and systemic innate immune markers are entangled in non–small cell lung cancer patients. • These markers have an impact on patient's clinical outcomes, mainly NKp30 receptor. • Higher NCR3 transcript (NKp30) is an independent prognostic factor of progression-free survival and overall survival. • Lower NCR3 is related to inflammatory status and is associated with poor outcomes. • Targeting these innate immune markers could represent a good therapeutic strategy. [ABSTRACT FROM AUTHOR]

Keywords: food allergy; eosinophilic esophagitis; innate cells; sensitization; cofactors; oral tolerance; microbiota EN food allergy eosinophilic esophagitis innate cells sensitization cofactors oral tolerance microbiota 1 3 3 06/14/21 20210610 NES 210610 Food allergy results from a failure to establish or maintain oral tolerance to certain food proteins and is manifested by adverse responses following ingestion of these foods that range from mild to life-threatening. In a food allergy model, blockade of PDI reduced small intestine mast cell numbers and activation and attenuated food allergy reactions. The Role of Basophils and Mast Cells Basophils and mast cells often take the center stage in food allergy as predominant effector cells in IgE-mediated responses. [Extracted from the article]

γδ T cells are non-conventional lymphocytes which show several properties of innate immune cells. They present a limited TCR repertoire and circulate as cells with a pre-activated phenotype thus being able to generate rapid immune responses. γδ T cells do not recognize classical peptide antigens, their TCRs are non-MHC restricted and they can respond to pathogen-associated molecular patterns and to cytokines in absence of TCR ligands. They also recognize self-molecules induced by stress, which indicate infection and cellular transformation. All these features let γδ T cells act as a first line of defense in sterile and non-sterile inflammation. γδ T cells represent 1–10% of circulating lymphocytes in the adult human peripheral blood, they are widely localized in non-lymphoid tissues and constitute the majority of immune cells in some epithelial surfaces, where they participate in the maintenance of the epithelial barriers. γδ T cells produce a wide range of cytokines that orchestrate the course of immune responses and also exert high cytotoxic activity against infected and transformed cells. In contrast to their beneficial role during infection, γδ T cells are also implicated in the development and progression of autoimmune diseases. Interestingly, several functions of γδ T cells are susceptible to modulation by interaction with other cells. In this review, we give an overview of the γδ T cell participation in infection and autoimmunity. We also revise the underlying mechanisms that modulate γδ T cell function that might provide tools to control pathological immune responses.

γδ T cells are non-conventional lymphocytes which show several properties of innate immune cells. They present a limited TCR repertoire and circulate as cells with a pre-activated phenotype thus being able to generate rapid immune responses. γδ T cells do not recognize classical peptide antigens, their TCRs are non-MHC restricted and they can respond to pathogen-associated molecular patterns and to cytokines in absence of TCR ligands. They also recognize self-molecules induced by stress, which indicate infection and cellular transformation. All these features let γδ T cells act as a first line of defense in sterile and non-sterile inflammation. γδ T cells represent 1–10% of circulating lymphocytes in the adult human peripheral blood, they are widely localized in non-lymphoid tissues and constitute the majority of immune cells in some epithelial surfaces, where they participate in the maintenance of the epithelial barriers. γδ T cells produce a wide range of cytokines that orchestrate the course of immune responses and also exert high cytotoxic activity against infected and transformed cells. In contrast to their beneficial role during infection, γδ T cells are also implicated in the development and progression of autoimmune diseases. Interestingly, several functions of γδ T cells are susceptible to modulation by interaction with other cells. In this review, we give an overview of the γδ T cell participation in infection and autoimmunity. We also revise the underlying mechanisms that modulate γδ T cell function that might provide tools to control pathological immune responses. [ABSTRACT FROM AUTHOR]

The interleukin (IL)-4 receptor alpha (IL-4Rα), ubiquitously expressed on both innate and adaptive immune cells, controls the signaling of archetypal type 2 immune regulators; IL-4 and IL-13, which elicit their signaling action by the type 1 IL-4Rα/gamma common and/or the type 2 IL-4Rα/IL-13Rα complexes. Global gene-deficient mouse models targeting IL-4, IL-13, or the IL-4Rα chain, followed by the development of conditional mice and generation of important cell-type-specific IL-4Rα-deficient mouse models, were indeed critical to gaining in-depth understanding of detrimental T helper (Th) 2 mechanisms in type 1-controlled diseases. A primary example being cutaneous leishmaniasis, which is caused by the protozoan parasite Leishmania major, among others. The disease is characterized by localized self-healing cutaneous lesions and necrosis for which, currently, not a single vaccine has made it to a stage that can be considered effective. The spectrum of human leishmaniasis belongs to the top 10 infectious diseases according to the World Health Organization. As such, 350 million humans are at risk of infection and disease, with an incidence of 1.5–2 million new cases being reported annually. A major aim of our research is to identify correlates of host protection and evasion, which may aid in vaccine design and therapeutic interventions. In this review, we focus on the immune-regulatory role of the IL-4Rα chain from innate immune responses to the development of beneficial type 1 and detrimental type 2 adaptive immune responses during cutaneous Leishmania infection. We discuss the cell-specific requirements of the IL-4Rα chain on crucial innate immune cells during L. major infection, including, IL-4Rα-responsive skin keratinocytes, macrophages, and neutrophils, as well as dendritic cells (DCs). The latter, contributing to one of the paradigm shifts with respect to the role of IL-4 instructing DCs in vivo, to promote Th1 responses against L. major. Finally, we extend these innate responses and mechanisms to control of adaptive immunity and the effect of IL-4Rα-responsiveness on T and B lymphocytes orchestrating the development of CD4+ Th1/Th2 and B effector 1/B effector 2 B cells in response to L. major infection in the murine host.

The global control of tuberculosis (TB) presents a continuous health challenge to mankind. Despite having effective drugs, TB still has a devastating impact on human health. Contributing reasons include the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the AIDS-pandemic, and the absence of effective vaccines against the disease. Indeed, alternative and effective methods of TB treatment and control are urgently needed. One such approach may be to more effectively engage the immune system; particularly the frontline pattern recognition receptor (PRR) systems of the host, which sense pathogen-associated molecular patterns (PAMPs) of Mtb. It is well known that 95% of individuals infected with Mtb in latent form remain healthy throughout their life. Therefore, we propose that clues can be found to control the remainder by successfully manipulating the innate immune mechanisms, particularly of nasal and mucosal cavities. This article highlights the importance of signaling through PRRs in restricting Mtb entry and subsequently preventing its infection. Furthermore, we discuss whether this unique therapy employing PRRs in combination with drugs can help in reducing the dose and duration of current TB regimen.

Previous studies suggested that the cross talk between NK cells and other cell types is crucial for the regulation of both innate and adaptive immune responses. In the present study, we analyzed the phenotypic and functional outcome of the interaction between resting or cytokine-activated NK cells and eosinophils derived from non-atopic donors. Our results provide the first evidence that a natural cytotoxicity receptor (NCR)/NCR ligand-dependent cross talk between NK cells and eosinophils may be important to upregulate the activation state and the effector function of cytokine-primed NK cells. This interaction also promotes the NK-mediated editing process of dendritic cells that influence the process of Th1 polarization. In turn, this cross talk also resulted in eosinophil activation and acquisition of the characteristic features of antigen-presenting cells. At higher NK/eosinophil ratios, cytokine-primed NK cells were found to kill eosinophils via NKp46 and NKp30, thus suggesting a potential immunoregulatory role for NK cells in dampening inflammatory responses involving eosinophils.

The interleukin (IL)-4 receptor alpha (IL-4Rα), ubiquitously expressed on both innate and adaptive immune cells, controls the signaling of archetypal type 2 immune regulators; IL-4 and IL-13, which elicit their signaling action by the type 1 IL-4Rα/gamma common and/or the type 2 IL-4Rα/IL-13Rα complexes. Global gene-deficient mouse models targeting IL-4, IL-13, or the IL-4Rα chain, followed by the development of conditional mice and generation of important cell-type-specific IL-4Rα-deficient mouse models, were indeed critical to gaining in-depth understanding of detrimental T helper (Th) 2 mechanisms in type 1-controlled diseases. A primary example being cutaneous leishmaniasis, which is caused by the protozoan parasite Leishmania major, among others. The disease is characterized by localized self-healing cutaneous lesions and necrosis for which, currently, not a single vaccine has made it to a stage that can be considered effective. The spectrum of human leishmaniasis belongs to the top 10 infectious diseases according to the World Health Organization. As such, 350 million humans are at risk of infection and disease, with an incidence of 1.5-2 million new cases being reported annually. A major aim of our research is to identify correlates of host protection and evasion, which may aid in vaccine design and therapeutic interventions. In this review, we focus on the immune-regulatory role of the IL-4Rα chain from innate immune responses to the development of beneficial type 1 and detrimental type 2 adaptive immune responses during cutaneous Leishmania infection. We discuss the cell-specific requirements of the IL-4Rα chain on crucial innate immune cells during L. major infection, including, IL-4Rα-responsive skin keratinocytes, macrophages, and neutrophils, as well as dendritic cells (DCs). The latter, contributing to one of the paradigm shifts with respect to the role of IL-4 instructing DCs in vivo, to promote Th1 responses against L. major. Finally, we extend these innate responses and mechanisms to control of adaptive immunity and the effect of IL-4Rα-responsiveness on T and B lymphocytes orchestrating the development of CD4+ Th1/Th2 and B effector 1/B effector 2 B cells in response to L. major infection in the murine host. [ABSTRACT FROM AUTHOR]

Summary Urinary tract infection (UTI) is the most common type of bacterial infection in humans. Fifty percent of all women will experience at least one UTI in their lifetime, with uropathogenic Escherichia coli (UPEC) accounting for 80% of reported cases. UTI evokes a complex, well-timed immune response that is crucial for bacterial clearance. The majority of immune cells participating in the immune response are absent from the healthy bladder, and the mechanisms used to recruit them upon UTI are not fully understood. Here, we show that immediately after UPEC infection, bladder epithelial cells secrete stromal cell-derived factor 1 (SDF-1), initiating immune cell accumulation at the site of infection. SDF-1 blockade significantly reduced immune cell migration to the infected bladder, resulting in severe exacerbation of infection. We also show that FimH, the adhesin of type 1 fimbria, one of UPEC’s virulence factors, is directly involved in the secretion of SDF-1 upon UTI. [ABSTRACT FROM AUTHOR]

Previous studies suggested that the cross talk between NK cells and other cell types is crucial for the regulation of both innate and adaptive immune responses. In the present study, we analyzed the phenotypic and functional outcome of the interaction between resting or cytokine-activated NK cells and eosinophils derived from non-atopic donors. Our results provide the first evidence that a natural cytotoxicity receptor (NCR)/NCR ligand-dependent cross talk between NK cells and eosinophils may be important to upregulate the activation state and the effector function of cytokine-primed NK cells. This interaction also promotes the NK-mediated editing process of dendritic cells that influence the process of Th1 polarization. In turn, this cross talk also resulted in eosinophil activation and acquisition of the characteristic features of antigen-presenting cells. At higher NK/eosinophil ratios, cytokine-primed NK cells were found to kill eosinophils via NKp46 and NKp30, thus suggesting a potential immunoregulatory role for NK cells in dampening inflammatory responses involving eosinophils. [ABSTRACT FROM AUTHOR]

Mycotic infections and their effect on the human condition have been widely overlooked and poorly surveilled by many health organizations even though mortality rates have increased in recent years. The increased usage of immunosuppressive and myeloablative therapies for the treatment of malignant as well as non-malignant diseases has contributed significantly to the increased incidence of fungal infections. Invasive fungal infections have been found to be responsible for at least 1.5 million deaths worldwide. About 90% of these deaths can be attributed to Cryptococcus, Candida, Aspergillus, and Pneumocystis. A better understanding of how the host immune system contains fungal infection is likely to facilitate the development of much needed novel antifungal therapies. Innate cells are responsible for the rapid recognition and containment of fungal infections and have been found to play essential roles in defense against multiple fungal pathogens. In this review we summarize our current understanding of host-fungi interactions with a focus on mechanisms of innate cell-mediated recognition and control of pulmonary aspergillosis.

Extracts of Viscum album (VA); a semi-parasitic plant, are frequently used in the complementary therapy of cancer and other immunological disorders. Various reports show that VA modulates immune system and exerts immune-adjuvant activities that might influence tumor regression. Currently, several therapeutic preparations of VA are available and hence an insight into the mechanisms of action of different VA preparations is necessary. In the present study, we performed a comparative study of five different preparations of VA on maturation and activation of human dendritic cells (DCs) and ensuing CD4+ T cell responses. Monocyte-derived human DCs were treated with VA Qu Spez, VA Qu Frf, VA M Spez, VA P and VA A. Among the five VA preparations tested VA Qu Spez, a fermented extract with a high level of lectins, significantly induced DC maturation markers CD83, CD40, HLA-DR and CD86, and secretion of pro-inflammatory cytokines such as IL-6, IL-8, IL-12 and TNF- . Furthermore, analysis of T cell cytokines in DC-T cell co-culture revealed that VA Qu Spez significantly stimulated IFN-γ secretion without modulating regulatory T cells and other CD4+ T cytokines IL-4, IL-13 and IL-17A. Our study thus delineates differential effects of VA preparations on DC maturation; function and T cell responses. [ABSTRACT FROM AUTHOR]

Mycotic infections and their effect on the human condition have been widely overlooked and poorly surveilled by many health organizations even though mortality rates have increased in recent years. The increased usage of immunosuppressive and myeloablative therapies for the treatment of malignant as well as non-malignant diseases has contributed significantly to the increased incidence of fungal infections. Invasive fungal infections have been found to be responsible for at least 1.5 million deaths worldwide. About 90% of these deaths can be attributed to Cryptococcus, Candida, Aspergillus, and Pneumocystis. A better understanding of how the host immune system contains fungal infection is likely to facilitate the development of much needed novel antifungal therapies. Innate cells are responsible for the rapid recognition and containment of fungal infections and have been found to play essential roles in defense against multiple fungal pathogens. In this review we summarize our current understanding of host-fungi interactions with a focus on mechanisms of innate cell-mediated recognition and control of pulmonary aspergillosis. [ABSTRACT FROM AUTHOR]

Abstract: The host and microbiota have evolved mechanisms for coexistence over millions of years. Accumulating evidence indicates that a dynamic mutualism between the host and the commensal microbiota has important implications for health, and microbial colonization contributes to the maintenance of intestinal immune homeostasis. However, alterations in communication between the mucosal immune system and gut microbial communities have been implicated as the core defect that leads to chronic intestinal inflammation and cancer development. We will discuss the recent progress on how gut microbiota regulates intestinal homeostasis and the pathogenesis of inflammatory bowel disease and colorectal cancer. [Copyright &y& Elsevier]

Highlights: [•] Innate cells contribute to the development of asthma features. [•] Epithelial cell–DC crosstalk is crucial for asthma development. [•] Epithelium-derived cytokines contribute to ILC2 responses. [•] Basophils have no role in Th2 sensitization to HDM, but contribute to the effector phase. [Copyright &y& Elsevier]

Given the time and resources invested in clinical trials, innovative prediction methods are needed to decrease late-stage failure in vaccine development. We identify combinations of early innate responses that predict neutralizing antibody (nAb) responses induced in HIV-Env SOSIP immunized cynomolgus macaques using various routes of vaccine injection and adjuvants. We analyze blood myeloid cells before and 24 h after each immunization by mass cytometry using a three-step clustering, and we discriminate unique vaccine signatures based on HLA-DR, CD39, CD86, CD11b, CD45, CD64, CD14, CD32, CD11c, CD123, CD4, CD16, and CADM1 surface expression. Various combinations of these markers characterize cell families positively associated with nAb production, whereas CADM1-expressing cells are negatively associated (p < 0.05). Our results demonstrate that monitoring immune signatures during early vaccine development could assist in identifying biomarkers that predict vaccine immunogenicity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The article focuses on the T cells' role in tumor regression. Immune cells can play both pro- and anti-tumoral roles infilterating solid tumors. As shown in the current model, T cells are placed as central actors of the antitumor immune action and they can kill tumor cells. Tumor growth is accelerated by depletion of circulating T cells in animals as per many murine tumor models.

Abstract: Among peripheral regulatory T cells, CD8+ T cells also play an important role in the maintenance of immune homeostasis. A subset of CD8+ Treg that express αβ T cell receptor (TCR) and CD8αα homodimers can recognize TCR-derived peptides in the context of the class Ib MHC molecule Qa-1. To gain a better understanding of the nature and phenotype of CD8αα+TCRαβ+ Treg, a global gene expression profiling using microarray, real-time quantitative polymerase chain reaction, and flow-cytometric analysis was performed using functional Treg clones and lines. The study findings show that CD8+ Treg shared gene profile expressed by innate-like lymphocytes, including murine intraepithelial lymphocytes and thymic CD8αα+TCRαβ+ T-cell populations. In addition, this subset displays differential expression of several key regulatory molecules, including CD200. CD8αα+ Treg expressed higher levels of a number of natural killer cell–related receptors and molecules belonging to the TNF superfamily. Collectively, peripheral class Ib-reactive CD8αα+TCRαβ+ T cells represent a unique regulatory population different from class Ia major histocompatibility complex–restricted conventional T cells. These studies have important implications for the regulatory mechanisms mediated by the CD8+ Treg population in general. [Copyright &y& Elsevier]

Atopic dermatitis (AD) is a chronic inflammatory skin disease known for its complex pathophysiology involving several immune pathways. In the lesion, signals from barrier disruption, allergens, and microbial colonization are integrated and transmitted to diverse immune cell types, which initiate and maintain the disease. Cytokines are critical in the allergic intercellular communication networks. This review focuses on up-to-date knowledge on the role of cytokines in AD, including recently described functions as well as novel cellular sources. We propose three modules defined as the cellular source of groups of cytokines: (1) keratinocytes, (2) innate immune cells, and (3) T cells. This view enables to better position the function of novel cytokine players, such as thymic stromal lymphopoetin, IL-21, IL-25, and IL-33, in linking different modules and ultimately leading to the allergic inflammatory phenotype. Persistent efforts in the detailed characterization of cytokine networks will be fundamental for the understanding of the complex pathogenic mechanisms of the disease and for guiding targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

Abstract: The primary inflammatory events occurring in the adipose tissue (AT) during high fat diet (HFD)-induced obesity are poorly defined. The present study was undertaken to characterize, in wild-type(+/+) and lymphocyte deficient RAG2(−/−) mice under HFD, the changes in AT immune cells by flow cytometry analyses. In (+/+) mice, early accumulation of AT B-cells was observed, followed by increased AT T-cell numbers and finally by the appearance of insulin resistance and AT macrophage accumulation. Lack of lymphocytes in the RAG2(−/−) mice did not affect the onset of obesity and the state of insulin resistance. However, a striking accumulation of AT NK cells and activated macrophages was detected. The present study demonstrates that AT is the site of an unexpected dynamic in innate and adaptive cells during diet-induced obesity and insulin resistance. Moreover it appears that early AT lymphocyte infiltration could be considered a protective process to temper adipose tissue inflammation. [Copyright &y& Elsevier]

Interleukin (IL)-22 is central to immune defense at barrier sites. We examined the contributions of innate lymphoid cell (ILC) and T cell-derived IL-22 during Citrobacter rodentium (C. r) infection using mice that both report Il22 expression and allow lineage-specific deletion. ILC-derived IL-22 activated STAT3 in C. r -colonized surface intestinal epithelial cells (IECs) but only temporally restrained bacterial growth. T cell-derived IL-22 induced a more robust and extensive activation of STAT3 in IECs, including IECs lining colonic crypts, and T cell-specific deficiency of IL-22 led to pathogen invasion of the crypts and increased mortality. This reflected a requirement for T cell-derived IL-22 for the expression of a host-protective transcriptomic program that included AMPs, neutrophil-recruiting chemokines, and mucin-related molecules, and it restricted IFNγ-induced proinflammatory genes. Our findings demonstrate spatiotemporal differences in the production and action of IL-22 by ILCs and T cells during infection and reveal an indispensable role for IL-22-producing T cells in the protection of the intestinal crypts. [Display omitted] • ILCs and T cells localize to distinct microanatomic niches during C.r infection • IL-22+ innate cells target surface IECs to limit early bacterial colonization • IL-22+ T cells target crypt IECs to prevent C.r dissemination into colonic crypts • IL-22+ T cells amplify IEC-derived host defense genes and repress IFN-induced genes Interleukin (IL)-22-producing innate and adaptive immune cells contribute to host protection at barrier sites. Zindl et al. reveal that IL-22+ ILCs and T cells are specialized for early versus late protection of the intestinal mucosa via distinct patterns of activation of intestinal epithelial cells: actions of ILCs are limited to the superficial IECs to limit early bacterial colonization, whereas IL-22+ CD4 T cells recruited to the LP uniquely target crypt IECs to restrain bacterial spread into the colonic crypts. [ABSTRACT FROM AUTHOR]

Keywords: inflammation; innate cells; mucosal pathology; mediators; homeostasis EN inflammation innate cells mucosal pathology mediators homeostasis 1 2 2 07/31/20 20200728 NES 200728 Cells of the innate immune system play an essential role in early protection against pathogens and tissue damage. To test this assumption, they used a new, sophisticated humanized mouse model with light-sheet fluorescence microscopic visualization, which enabled them to assess whether human ILC2 cells had accumulated in the lung following papain-induced airway inflammation. Inflammation, innate cells, mucosal pathology, mediators, homeostasis. [Extracted from the article]