The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.

Smoking changes adaptive immunity with persistent effects.

Individuals differ widely in their immune responses, with age, sex and genetic factors having major roles in this inherent variability1-6. However, the variables that drive such differences in cytokine secretion-a crucial component of the host response to immune challenges-remain poorly defined. Here we investigated 136 variables and identified smoking, cytomegalovirus latent infection and body mass index as major contributors to variability in cytokine response, with effects of comparable magnitudes with age, sex and genetics. We find that smoking influences both innate and adaptive immune responses. Notably, its effect on innate responses is quickly lost after smoking cessation and is specifically associated with plasma levels of CEACAM6, whereas its effect on adaptive responses persists long after individuals quit smoking and is associated with epigenetic memory. This is supported by the association of the past smoking effect on cytokine responses with DNA methylation at specific signal trans-activators and regulators of metabolism. Our findings identify three novel variables associated with cytokine secretion variability and reveal roles for smoking in the short- and long-term regulation of immune responses. These results have potential clinical implications for the risk of developing infections, cancers or autoimmune diseases.

The function of γδ T cells in humoral immune responses.

PURPOSE: The purpose of this review is to discuss the role of γδ T cells played in humoral immune responses. BACKGROUND: The γδ T cell receptor (γδ TCR) recognizes antigens, including haptens and proteins, in an MHC-independent manner. The recognition of these antigens by γδ TCRs crosses antigen recognition by the B cell receptors (BCRs), suggesting that γδ T cells may be involved in the process of antigen recognition and activation of B cells. However, the role of γδ T cells in humoral immune responses is still less clear. METHODS: The kinds of literature about the γδ T cell-B cell interaction were searched on PubMed with search terms, such as γδ T cells, antibody, B cell responses, antigen recognition, and infection. RESULTS: Accumulating evidence indicates that γδ T cells, independent of αß T cells, participate in multiple steps of humoral immunity, including B cell maturation, activation and differentiation, antibody production and class switching. Mechanically, γδ T cells affect B cell function by directly interacting with B cells, secreting cytokines, or modulating αß T cells. CONCLUSION: In this review, we summarize current knowledge on how γδ T cells take part in the humoral immune response, which may assist future vaccine design.

Functional T cells are capable of supernumerary cell division and longevity.

Differentiated somatic mammalian cells putatively exhibit species-specific division limits that impede cancer but may constrain lifespans1-3. To provide immunity, transiently stimulated CD8+ T cells undergo unusually rapid bursts of numerous cell divisions, and then form quiescent long-lived memory cells that remain poised to reproliferate following subsequent immunological challenges. Here we addressed whether T cells are intrinsically constrained by chronological or cell-division limits. We activated mouse T cells in vivo using acute heterologous prime-boost-boost vaccinations4, transferred expanded cells to new mice, and then repeated this process iteratively. Over 10 years (greatly exceeding the mouse lifespan)5 and 51 successive immunizations, T cells remained competent to respond to vaccination. Cells required sufficient rest between stimulation events. Despite demonstrating the potential to expand the starting population at least 1040-fold, cells did not show loss of proliferation control and results were not due to contamination with young cells. Persistent stimulation by chronic infections or cancer can cause T cell proliferative senescence, functional exhaustion and death6. We found that although iterative acute stimulations also induced sustained expression and epigenetic remodelling of common exhaustion markers (including PD1, which is also known as PDCD1, and TOX) in the cells, they could still proliferate, execute antimicrobial functions and form quiescent memory cells. These observations provide a model to better understand memory cell differentiation, exhaustion, cancer and ageing, and show that functionally competent T cells can retain the potential for extraordinary population expansion and longevity well beyond their organismal lifespan.

Analysis of the Toll and Spaetzle Genes Involved in Toll Pathway-Dependent Antimicrobial Gene Induction in the Red Flour Beetle, Tribolium castaneum (Coleoptera; Tenebrionidae).

Insects rely only on their innate immune system to protect themselves from pathogens. Antimicrobial peptide (AMP) production is the main immune reaction in insects. In Drosophila melanogaster, the reaction is regulated mainly by the Toll and immune deficiency (IMD) pathways. Spaetzle proteins, activated by immune signals from upstream components, bind to Toll proteins, thus, activating the Toll pathway, which in turn, induces AMP genes. Previous studies have shown the difference in immune systems related to Toll and IMD pathways between D. melanogaster and Tribolium castaneum. In T. castaneum, nine Toll and seven spaetzle (spz) genes were identified. To extend our understanding of AMP production by T. castaneum, we conducted functional assays of Toll and spaetzle genes related to Toll-pathway-dependent AMP gene expression in T. castaneum under challenge with bacteria or budding yeast. The results revealed that Toll3 and Toll4 double-knockdown and spz7 knockdown strongly and moderately reduced the Toll-pathway-dependent expression of AMP genes, respectively. Moreover, Toll3 and Toll4 double-knockdown pupae more rapidly succumbed to entomopathogenic bacteria than the control pupae, but spz7 knockdown pupae did not. The results suggest that Toll3 and Toll4 play a large role in Toll-pathway-dependent immune reactions, whereas spz7 plays a small part.

Dual Immune Regulatory Roles of Interleukin-33 in Pathological Conditions.

Interleukin-33 (IL-33), a member of the IL-1 cytokine family and a multifunctional cytokine, plays critical roles in maintaining host homeostasis and in pathological conditions, such as allergy, infectious diseases, and cancer, by acting on multiple types of immune cells and promoting type 1 and 2 immune responses. IL-33 is rapidly released by immune and non-immune cells upon stimulation by stress, acting as an "alarmin" by binding to its receptor, suppression of tumorigenicity 2 (ST2), to trigger downstream signaling pathways and activate inflammatory and immune responses. It has been recognized that IL-33 displays dual-functioning immune regulatory effects in many diseases and has both pro- and anti-tumorigenic effects, likely depending on its primary target cells, IL-33/sST2 expression levels, cellular context, and the cytokine microenvironment. Herein, we summarize our current understanding of the biological functions of IL-33 and its roles in the pathogenesis of various conditions, including inflammatory and autoimmune diseases, infections, cancers, and cases of organ transplantation. We emphasize the nature of context-dependent dual immune regulatory functions of IL-33 in many cells and diseases and review systemic studies to understand the distinct roles of IL-33 in different cells, which is essential to the development of more effective diagnoses and therapeutic approaches for IL-33-related diseases.

PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells.

Expansion and differentiation of antigen-experienced PD-1+TCF-1+ stem-like CD8+ T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade1-4. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of 'better effector' CD8+ T cells similar to those generated in an acute infection5. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor ß- and γ-chain (IL-2Rßγ)-biased agonists are currently being developed6-10. Here we show that IL-2Rßγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rßγ on the same cell recovers the ability to differentiate stem-like CD8+ T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

A comprehensive review of chemokine CXC17 (VCC1) in cancer, infection, and inflammation.

A crucial component of the immune system are chemokiness. Chemokine's dysregulation has been linked to a number of pathological diseases. Recently, CXCL17, a chemokine belonging to the CXC subfamily, was identified. With regard to a number of physiological conditions and disorders, CXCL17 either has homeostatic or pathogenic effects. Some research suggests that CXCL17 is an orphan ligand, despite the fact that G protein-coupled receptor (GPR) 35 has been suggested as a possible receptor for CXCL17. Since CXCL17 is primarily secreted by mucosal epithelia, such as those in the digestive and respiratory tracts, under physiological circumstances, this chemokine is referred to as a mucosal chemokine. Macrophages and monocytes are the cells that express GPR35 and hence react to CXCL17. In homeostatic conditions, this chemokine has anti-inflammatory, antibacterial, and chemotactic properties. CXCL17 promotes angiogenesis, metastasis, and cell proliferation in pathologic circumstances like malignancies. However, other studies suggest that CXCL17 may have anti-tumor properties. Additionally, studies have shown that CXCL17 may have a role in conditions such as idiopathic pulmonary fibrosis, multiple sclerosis, asthma, and systemic sclerosis. Additionally, deregulation of CXCL17 in some diseases may serve as a biomarker for diagnosis and prognosis. Clarifying the underlying mechanism of CXCL17's activity in homeostatic and pathological situations may thus increase our understanding of its role and hold promise for the development of novel treatment strategies.

LPA suppresses T cell function by altering the cytoskeleton and disrupting immune synapse formation.

Cancer and chronic infections often increase levels of the bioactive lipid, lysophosphatidic acid (LPA), that we have demonstrated acts as an inhibitory ligand upon binding LPAR5 on CD8 T cells, suppressing cytotoxic activity and tumor control. This study, using human and mouse primary T lymphocytes, reveals how LPA disrupts antigen-specific CD8 T cell:target cell immune synapse (IS) formation and T cell function via competing for cytoskeletal regulation. Specifically, we find upon antigen-specific T cell:target cell formation, IP3R1 localizes to the IS by a process dependent on mDia1 and actin and microtubule polymerization. LPA not only inhibited IP3R1 from reaching the IS but also altered T cell receptor (TCR)­induced localization of RhoA and mDia1 impairing F-actin accumulation and altering the tubulin code. Consequently, LPA impeded calcium store release and IS-directed cytokine secretion. Thus, targeting LPA signaling in chronic inflammatory conditions may rescue T cell function and promote antiviral and antitumor immunity.

Cross Talk Between Natural Killer T and Dendritic Cells and Its Impact on T Cell Responses in Infections.

Both innate and adaptive immunity is vital for host defense against infections. Dendritic cells (DCs) are critical for initiating and modulating adaptive immunity, especially for T-cell responses. Natural killer T (NKT) cells are a small population of innate-like T cells distributed in multiple organs. Many studies have suggested that the cross-talk between these two immune cells is critical for immunobiology and host defense mechanisms. Not only can DCs influence the activation/function of NKT cells, but NKT cells can feedback on DCs also, thus modulating the phenotype and function of DCs and DC subsets. This functional feedback of NKT cells on DCs, especially the preferential promoting effect on CD8α+ and CD103+ DC subsets in lymphoid and non-lymphoid tissues, significantly impacts the systemic and local adaptive CD4 and CD8 T cell responses in infections. This review focuses on the two-way interaction between NKT cells and DCs, emphasizing the importance of NKT cell feedback on DCs in bridging innate and adaptive immune responses for host defense purposes.

The Multifaceted Roles of Mast Cells in Immune Homeostasis, Infections and Cancers.

Mast cells (MCs) play important roles in normal immune responses and pathological states. The location of MCs on the boundaries between tissues and the external environment, including gut mucosal surfaces, lungs, skin, and around blood vessels, suggests a multitude of immunological functions. Thus, MCs are pivotal for host defense against different antigens, including allergens and microbial pathogens. MCs can produce and respond to physiological mediators and chemokines to modulate inflammation. As long-lived, tissue-resident cells, MCs indeed mediate acute inflammatory responses such as those evident in allergic reactions. Furthermore, MCs participate in innate and adaptive immune responses to bacteria, viruses, fungi, and parasites. The control of MC activation or stabilization is a powerful tool in regulating tissue homeostasis and pathogen clearance. Moreover, MCs contribute to maintaining the homeostatic equilibrium between host and resident microbiota, and they engage in crosstalk between the resident and recruited hematopoietic cells. In this review, we provide a comprehensive overview of the functions of MCs in health and disease. Further, we discuss how mouse models of MC deficiency have become useful tools for establishing MCs as a potential cellular target for treating inflammatory disorders.

Inflammation and infection in plasma cell disorders: how pathogens shape the fate of patients.

The role of infection and chronic inflammation in plasma cell disorders (PCD) has been well-described. Despite not being a diagnostic criterion, infection is a common complication of most PCD and represents a significant cause of morbidity and mortality in this population. As immune-based therapeutic agents are being increasingly used in multiple myeloma, it is important to recognize their impact on the epidemiology of infections and to identify preventive measures to improve outcomes. This review outlines the multiple factors attributed to the high infectious risk in PCD (e.g. the underlying disease status, patient age and comorbidities, and myeloma-directed treatment), with the aim of highlighting future prophylactic and preventive strategies that could be implemented in the clinic. Beyond this, infection and pathogens as an entity are believed to also influence disease biology from initiation to response to treatment and progression through a complex interplay involving pathogen exposure, chronic inflammation, and immune response. This review will outline both the direct and indirect role played by oncogenic pathogens in PCD, highlight the requirement for large-scale studies to decipher the precise implication of the microbiome and direct pathogens in the natural history of myeloma and its precursor disease states, and understand how, in turn, pathogens shape plasma cell biology.

Modulation of Macrophage Immunometabolism: A New Approach to Fight Infections.

Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to extracellular cues and to adopt different phenotypes and functions in response to these stimuli. The evidence accumulated in the last decade has highlighted the crucial role of metabolic reprogramming during macrophage activation in infectious context. Thus, understanding and manipulation of macrophage immunometabolism during infection could be of interest to develop therapeutic strategies. In this review, we focus on 5 major metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis, tricarboxylic acid cycle and amino acid metabolism and discuss how they sustain and regulate macrophage immune function in response to parasitic, bacterial and viral infections as well as trained immunity. At the end, we assess whether some drugs including those used in clinic and in development can target macrophage immunometabolism for potential therapy during infection with an emphasis on SARS-CoV2 infection.

Infections, Reactions of Natural Killer T Cells and Natural Killer Cells, and Kidney Injury.

Natural killer T (NKT) cells and NK cells are representative innate immune cells that perform antitumor and antimicrobial functions. The involvement of these cells in various renal diseases, including acute kidney injury (AKI), has recently become evident. Murine NKT cells are activated and cause AKI in response to various stimuli, such as their specific ligand, cytokines, and bacterial components. Both renal vascular endothelial cell injury (via the perforin-mediated pathway) and tubular epithelial cell injury (via the tumor necrosis factor-alpha/Fas ligand pathway) are independently involved in the pathogenesis of AKI. NK cells complement the functions of NKT cells, thereby contributing to the development of infection-associated AKI. Human CD56+ T cells, which are a functional counterpart of murine NKT cells, as well as a subpopulation of CD56+ NK cells, strongly damage intrinsic renal cells in vitro upon their activation, possibly through mechanisms similar to those in mice. These cells are also thought to be involved in the acute exacerbation of pre-existing glomerulonephritis triggered by infection in humans, and their roles in sepsis-associated AKI are currently under investigation. In this review, we will provide an overview of the recent advances in the understanding of the association among infections, NKT and NK cells, and kidney injury, which is much more profound than previously considered. The important role of liver macrophages in the activation of NKT cells will also be introduced.

Adenosine receptor 2a agonists target mouse CD11c+T-bet+ B cells in infection and autoimmunity.

CD11c+T-bet+ B cells are recognized as an important component of humoral immunity and autoimmunity. These cells can be distinguished from other B cells by their higher expression of the adenosine receptor 2a. Here we address whether A2A receptor activation can affect CD11c+T-bet+ B cells. We show that administration of the A2A receptor agonist CGS-21680 depletes established CD11c+T-bet+ B cells in ehrlichial-infected mice, in a B cell-intrinsic manner. Agonist treatment similarly depletes CD11c+T-bet+ B cells and CD138+ B cells and reduces anti-nuclear antibodies in lupus-prone mice. Agonist treatment is also associated with reduced kidney pathology and lymphadenopathy. Moreover, A2A receptor stimulation depletes pathogenic lymphocytes and ameliorates disease even after disease onset, highlighting the therapeutic potential of this treatment. This study suggests that targeting the adenosine signaling pathway may provide a method for the treatment of lupus and other autoimmune diseases mediated by T-bet+ B cells.

Inhibition of NETosis for treatment purposes: friend or foe?

Active neutrophils participate in innate and adaptive immune responses through various mechanisms, one of the most important of which is the formation and release of neutrophil extracellular traps (NETs). The NETs are composed of network-like structures made of histone proteins, DNA and other released antibacterial proteins by activated neutrophils, and evidence suggests that in addition to the innate defense against infections, NETosis plays an important role in the pathogenesis of several other non-infectious pathological states, such as autoimmune diseases and even cancer. Therefore, targeting NET has become one of the important therapeutic approaches and has been considered by researchers. NET inhibitors or other molecules involved in the NET formation, such as the protein arginine deiminase 4 (PAD4) enzyme, an arginine-to-citrulline converter, participate in chromatin condensation and NET formation, is the basis of this therapeutic approach. The important point is whether complete inhibition of NETosis can be helpful because by inhibiting this mechanism, the activity of neutrophils is suppressed. In this review, the biology of NETosis and its role in the pathogenesis of some important diseases have been summarized, and the consequences of treatment based on inhibition of NET formation have been discussed.

Adverse effects in hematologic malignancies treated with chimeric antigen receptor (CAR) T cell therapy: a systematic review and Meta-analysis.

BACKGROUND: Recently, chimeric antigen receptor-modified (CAR) T cell therapy for hematological malignancies has shown clinical efficacy. Hundreds of clinical trials have been registered and lots of studies have shown hematologic toxic effects were very common. The main purpose of this review is to systematically analyze hematologic toxicity in hematologic malignancies treated with CAR-T cell therapy. METHODS: We searched databases including PubMed, Web of Science, Embase and Cochrane up to January 2021. For safety analysis of overall hematologic toxicity, the rate of neutrophil, thrombocytopenia and anemia were calculated. Subgroup analysis was performed for age, pathological type, target antigen, co-stimulatory molecule, history of hematopoietic stem cell transplantation (HSCT) and prior therapy lines. The incidence rate of aspartate transferase (AST) increased, alanine transaminase (ALT) increased, serum creatine increased, APTT prolonged and fibrinogen decreased were also calculated. RESULTS: Overall, 52 studies involving 2004 patients were included in this meta-analysis. The incidence of any grade neutropenia, thrombocytopenia and anemia was 80% (95% CI: 68-89%), 61% (95% CI: 49-73%), and 68% (95%CI: 54-80%) respectively. The incidences of grade ≥ 3 neutropenia, thrombocytopenia and anemia were 60% (95% CI: 49-70%), 33% (95% CI: 27-40%), and 32% (95%CI: 25-40%) respectively. According to subgroup analysis and the corresponding Z test, hematological toxicity was more frequent in younger patients, in patients with ≥4 median lines of prior therapy and in anti-CD19 cases. The subgroup analysis of CD19 CAR-T cell constructs showed that 41BB resulted in less hematological toxicity than CD28. CONCLUSION: CAR-T cell therapy has dramatical efficacy in hematological malignancies, but the relevant adverse effects remain its obstacle. The most common ≥3 grade side effect is hematological toxicity, and some cases die from infections or severe hemorrhage in early period. In long-term follow-up, hematological toxicity is less life-threatening generally and most suffered patients recover to adequate levels after 3 months. To prevent life-threatening infections or bleeding events, clinicians should pay attention to intervention of hematological toxicity in the early process of CAR-T cell therapy.

Genetic characterizations of Toll-like receptors in the brown rat and their associations with pathogen infections.

Toll-like receptors (TLRs) are important initiators of innate immune responses that target host-pathogen interactions. However, further research into the molecular characteristics of TLRs in wild populations is required, as well as how TLRs genetically influenced pathogen infections in the brown rat (Rattus norvegicus). Here, we explored the genetic characterization and evolution of 2 sensing nucleic acid TLRs (TLR7 and TLR8) and 2 sensing non-nucleic acid TLRs (TLR2 and TLR4) in the wild brown rat, and assessed their associations with 2 RNA viruses (Seoul hantavirus and rat hepatitis E virus (HEV)) and 2 bacteria (Leptospira and Bartonella). In these 4 TLRs, we discovered a total of 16 variants. Furthermore, TLR8 had high genetic diversity among 7 variants, while TLR2 had low genetic diversity with only 1 variant. According to selective pressure analyses, TLR4, TLR7, and TLR8 genes evolved under purifying selection. Interestingly, significant associations were found between 3 TLR8 variants and HEV infection, as well as 1 TLR2 variant and Bartonella infection. Overall, our findings provided a glimpse into the genetic characterization of TLRs in the brown rat, and further demonstrated that TLR2 and TLR8 genetic variations were related to Bartonella and HEV infection, respectively. Especially, TLR8 may be a good candidate immune gene for future research on molecular ecology and functional adaptation in wild populations.

The Role of Angiotensin-Converting Enzyme in Immunity: Shedding Light on Experimental Findings.

Angiotensin-converting enzyme (ACE) is a zinc-dependent dicarboxypeptidase with two catalytic components, which has an important role in regulating blood pressure by converting angiotensin I to angiotensin II. ACE breaks down other peptides besides angiotensin I and has a variety of physiological effects together with renal growth and reproduction in men. ACE also acts on innate and acquired immune systems by affecting macrophage and neutrophil function, and these outcomes are exacerbated due to the overexpression of ACE. Overexpression of ACE in macrophages imposes antitumor and antimicrobial response, and it enhances the ability of neutrophils to produced super peroxide that has a bactericidal effect. ACE is also known to contribute to the expression of Major Histocompatibility Complex (MHC) class I and MHC class II peptides through enzymatic alterations of these peptides. Apprehending the expression of ACE and its effects on myeloid cell (myelogenous cells) activity can be promising in therapeutic interventions, including treatment of infection and malignancy.