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Roughly one-half of mice with partial defects in two immune tolerance pathways (AireGW/+Lyn-/- mice) spontaneously develop severe damage to their retinas due to T cell reactivity to Aire-regulated interphotoreceptor retinoid-binding protein (IRBP). Single-cell T cell receptor (TCR) sequencing of CD4+ T cells specific for a predominate epitope of IRBP showed a remarkable diversity of autoantigen-specific TCRs with greater clonal expansions in mice with disease. TCR transgenic mice made with an expanded IRBP-specific TCR (P2.U2) of intermediate affinity exhibited strong but incomplete negative selection of thymocytes. This negative selection was absent in IRBP-/- mice and greatly defective in AireGW/+ mice. Most P2.U2+/- mice and all P2.U.2+/-AireGW/+ mice rapidly developed inflammation of the retina and adjacent uvea (uveitis). Aire-dependent IRBP expression in the thymus also promoted Treg differentiation, but the niche for this fate determination was small, suggesting differences in antigen presentation leading to negative selection vs. thymic Treg differentiation and a stronger role for negative selection in preventing autoimmune disease in the retina. [ABSTRACT FROM AUTHOR]

T cell receptor (TCR) transgenic mice represent an invaluable tool to study antigen-specific immune responses. In the pre-existing models, a monoclonal TCR is driven by a non-physiologic promoter and randomly integrated into the genome. Here, we create a highly efficient methodology to develop T cell receptor exchange (TRex) mice, in which TCRs, specific to the self/tumor antigen mesothelin (Msln), are integrated into the Trac locus, with concomitant Msln disruption to circumvent T cell tolerance. We show that high affinity TRex thymocytes undergo all sequential stages of maturation, express the exogenous TCR at DN4, require MHC class I for positive selection and undergo negative selection only when both Msln alleles are present. By comparison of TCRs with the same specificity but varying affinity, we show that Trac targeting improves functional sensitivity of a lower affinity TCR and confers resistance to T cell functional loss. By generating P14 TRex mice with the same specificity as the widely used LCMV-P14 TCR transgenic mouse, we demonstrate increased avidity of Trac-targeted TCRs over transgenic TCRs, while preserving physiologic T cell development. Together, our results support that the TRex methodology is an advanced tool to study physiological antigen-specific T cell behavior. The currently available transgenic T cell receptor (TCR) models represent high affinity antigen-TCR interactions. Authors here present an alternative approach to target an exogenous TCR into the physiological Trac locus in the germline of mice, which uncovers that the natural genomic context for TCRs can enhance the antigen sensitivity of lower affinity TCRs and enables the physiologic range of antigen-TCR interaction and a gene dosage dependent mechanism of central tolerance. [ABSTRACT FROM AUTHOR]

Myocarditis is an inflammatory disease of the myocardium with heterogeneous etiology, clinical presentation, and prognosis; when it is associated with myocardial dysfunction, this identifies the entity of inflammatory cardiomyopathy. In the last few decades, the relevance of the immune system in myocarditis onset and progression has become evident, thus having crucial clinical relevance in terms of treatment and prognostic stratification. In fact, the advances in cardiac immunology have led to a better characterization of the cellular subtypes involved in the pathogenesis of inflammatory cardiomyopathy, whether the etiology is infectious or autoimmune/immune-mediated. The difference in the clinical course between spontaneous recovery to acute, subacute, or chronic progression to end-stage heart failure may be explained not only by classical prognostic markers but also through immune-pathological mechanisms at a cellular level. Nevertheless, much still needs to be clarified in terms of immune characterization and molecular mechanisms especially in biopsy-proven myocarditis. The aims of this review are to (1) describe inflammatory cardiomyopathy etiology, especially immune-mediated/autoimmune forms, (2) analyze recent findings on the role of different immune cells subtypes in myocarditis, (3) illustrate the potential clinical relevance of such findings, and (4) highlight the need of further studies in pivotal areas of myocarditis cellular immunology. [ABSTRACT FROM AUTHOR]

Superantigens (sAgs) are bacterial virulence factors that induce a state of immune hyperactivation by forming a bridge between certain subsets of T cell receptor (TCR) β chains on T lymphocytes, and class II major histocompatibility complex (MHC-II) molecules; this cross-linking leads to indiscriminate T cell activation, cytokine storm and toxic shock. Here we show that sAg exposure drives the preferential expansion of naive and central memory T cell subsets, but not effector or resident memory T cells, which instead, hyper release pro-inflammatory cytokines. A targeted therapeutic approach to minimise cytokine release by effector memory T cells attenuated sAg-induced cytokine release. Irrespective of antigen experience, sAg activation does not render mature T cells permanently dysfunctional, and full restoration of effector function is observed following a transient and reversible anergy. Moreover, we show that in the face of sAg induced immune hyperactivation, an intact bacterium-specific CD4+ T cell response can be mounted.Bacterial superantigens (sAg) have been shown to induce T cell hyperactivation through cross linking between MHC class II on antigen presenting cells and certain TCRs on T lymphocytes. Here the authors explore how sAg impacts CD4 and CD8 T cell subsets, leading to either expansion or excessive release of pro-inflammatory cytokines and they observe that a temporary state of anergy can occur, while bacterium-specific T cells continue to be generated [ABSTRACT FROM AUTHOR]

Introduction: In this study, we report a novel therapeutic approach redirecting antigen-specific CD4+ T cells recognizing a hybrid insulin peptide (BDC2.5 T cell receptor (TCR) transgenic CD4+ T cells) to attract and suppress islet-specific CD8+ T cells T cells in the non-obese diabetic (NOD) mouse model, and prevent the development of autoimmune diabetes. Methods: Purified BDC2.5 CD4+ T cells were induced to differentiate into regulatory T cells (Tregs). The Tregs were then electroporated with mRNA encoding chimeric human β2 microglobulin (hβ 2m) covalently linked to insulin B chain amino acids 15-23 (designated INS-eTreg) or islet-specific glucose-6- phosphatase related protein (IGRP) peptide 206-214 (designated IGRP-eTreg). Immunoregulatory functions of these engineered regulatory T cells (eTregs) were tested by in vitro assays and in vivo co-transfer experiments with β-cell-antigen-specific CD8+ T cells in NOD.Scid mice or by adoptive transfer into young, pre-diabetic NOD mice. Results: These eTregs were phenotyped by flow cytometry, and shown to have high expression of FoxP3, as well as other markers of Treg function, including IL- 10. They suppressed polyclonal CD4+ T cells and antigen-specific CD8+ T cells (recognizing insulin or IGRP), decreasing proliferation and increasing exhaustion and regulatory markers in vitro. In vivo, eTregs reduced diabetes development in co-transfer experiments with pathogenic antigen-specific CD8+ T cells (INS- CD8+ or IGRP-CD8+ cells) into NOD.Scid mice. Finally, when the eTreg were injected into young NOD mice, they reduced insulitis and prevented spontaneous diabetes in the recipient mice. Conclusion: Our results suggest a novel therapeutic strategy to protect NOD mice by targeting antigen-specific cytotoxic CD8+ T cells, using redirected antigen-specific CD4+ Treg cells, to suppress autoimmune diabetes. This may suggest an innovative therapy for protection of people at risk of development of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Chlamydiae are bacteria that are intriguing and important at the same time. The genus Chlamydia encompasses many species of obligate intracellular organisms: they can multiply only inside the cells of their host organism. Many, perhaps most animals have their own specifically adapted chlamydial species. In humans, the clinically most relevant species is Chlamydia trachomatis, which has particular importance as an agent of sexually transmitted disease. Pigs are the natural host of Chlamydia suis but may also carry Chlamydia abortus and Chlamydia pecorum. C. abortus and possibly C. suis have anthropozoonotic potential, which makes them interesting to human medicine, but all three species bring a substantial burden of disease to pigs. The recent availability of genomic sequence comparisons suggests adaptation of chlamydial species to their respective hosts. In cell biological terms, many aspects of all the species seem similar but non-identical: the bacteria mostly replicate within epithelial cells; they are taken up by the host cell in an endosome that they customize to generate a cytosolic vacuole; they have to evade cellular defences and have to organize nutrient transport to the vacuole; finally, they have to organize their release to be able to infect the next cell or the next host. What appears to be very difficult and challenging to achieve, is in fact a greatly successful style of parasitism. I will here attempt to cover some of the aspects of the infection biology of Chlamydia, from cell biology to immune defence, epidemiology and possibilities of prevention. I will discuss the pig as a host species and the species known to infect pigs but will in particular draw on the more detailed knowledge that we have on species that infect especially humans. [ABSTRACT FROM AUTHOR]

Th1 and Th2 cytokines determine the outcome of Leishmania major infection and immune protection depends mainly on memory T cells induced during vaccination. This largely hinges on the nature and type of memory T cells produced. In this study, transgenic Leishmania major strains expressing membrane-associated ovalbumin (mOVA) and soluble ovalbumin (sOVA) were used as a model to study whether fully differentiated Th1/Th2 and Th17 cells can recall immune memory and tolerate pathogen manipulation. Naïve OT-II T cells were polarised in vitro into Th1/Th2 cells, and these cells were transferred adoptively into recipient mice. Following the transferral of the memory cells, the recipient mice were challenged with OVA transgenic Leishmania major and a wild-type parasite was used a control. The in vitro-polarised T helper cells continued to produce the same cytokine signatures after being challenged by both forms of OVA-expressing Leishmania major parasites in vivo. This suggests that antigen-experienced cells remain the same or unaltered in the face of OVA-transgenic Leishmania major. Such ability of these antigen-experienced cells to remain resilient to manipulation by the parasite signifies that vaccines might be able to produce immune memory responses and defend against parasitic immune manipulation in order to protect the host from infection. [ABSTRACT FROM AUTHOR]

The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator–activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity. Editor's summary: After initial antigen encounter, some T cells persist and differentiate into long-lived memory cells. This process is accompanied by metabolic reprogramming that supports survival and memory functions, but the key factors driving memory T cell metabolic adaptation remain unclear. Using mouse models of viral infection and melanoma, Bevilacqua et al. found that the nuclear receptor peroxisome proliferator–activated receptor β/δ (PPARβ/δ) supports the switch from aerobic glycolysis to oxidative metabolism during central memory CD8+ T cell formation. PPARβ/δ expression was required for memory T cell responses upon rechallenge, as well as the generation of TCF-1+ progenitor exhausted T cells during chronic antigen exposure. Together, these findings identify PPARβ/δ as a key regulator of metabolic reprogramming during memory T cell differentiation. —Claire Olingy [ABSTRACT FROM AUTHOR]

From established latency, human herpes virus type 2 (HSV-2) frequently reactivates into the genital tract, resulting in symptomatic ulcers or subclinical shedding. Tissue-resident memory (TRM) CD8+ T cells that accumulate and persist in the genital skin at the local site of recrudescence are the "first responders" to viral reactivation, performing immunosurveillance and containment and aborting the ability of the virus to induce clinical lesions. This review describes the unique spatiotemporal characteristics, transcriptional signatures, and noncatalytic effector functions of TRM CD8+ T cells in the tissue context of human HSV-2 infection. We highlight recent insights into the intricate overlaps between intrinsic resistance, innate defense, and adaptive immunity in the tissue microenvironment and discuss how rapid virus–host dynamics at the skin and mucosal level influence clinical outcomes of genital herpes diseases. [ABSTRACT FROM AUTHOR]

Insulin is a central autoantigen in the pathogenesis of T1D, and thymic epithelial cell expression of insulin under the control of the Autoimmune Regulator (Aire) is thought to be a key component of maintaining tolerance to insulin. In spite of this general working model, direct detection of this thymic selection on insulin-specific T cells has been somewhat elusive. Here, we used a combination of highly sensitive T cell receptor transgenic models for detecting thymic selection and sorting and sequencing of Insulin-specific CD4+ T cells from Aire-deficient mice as a strategy to further define their selection. This analysis revealed a number of unique t cell receptor (TCR) clones in Aire-deficient hosts with high affinity for insulin/major histocompatibility complex (MHC) ligands. We then modeled the thymic selection of one of these clones in Aire-deficient versus wild-type hosts and found that this model clone could escape thymic negative selection in the absence of thymic Aire. Together, these results suggest that thymic expression of insulin plays a key role in trimming and removing high-affinity insulin-specific T cells from the repertoire to help promote tolerance. [ABSTRACT FROM AUTHOR]

Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rβ–IL2Rγc membrane dimers. This results in impaired IL-2–mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.Prostaglandin E2 from the tumour microenvironment impairs interleukin-2 sensing by tumour-infiltrating lymphocytes, restricting proliferative response and promoting T cell death via metabolic impairment and ferroptosis. [ABSTRACT FROM AUTHOR]

Anthriscus sylvestris (L.) Hoffm. (Apiaceae), commonly known as wild chervil, has gained scientific interest owing to its diverse phytochemical profile and potential therapeutic applications. The plant, despite being categorized as a noxious weed, is traditionally used in treating various conditions like headaches, dressing wounds, and as a tonic, antitussive, antipyretic, analgesic, and diuretic. Its pharmacological importance stems from containing diverse bioactive lignans, especially aryltetralins and dibenzylbutyrolactones. One of the main compounds of A. sylvestris, deoxypodophyllotoxin, among its wide-ranging effects, including antitumor, antiproliferative, antiplatelet aggregation, antiviral, anti-inflammatory, and insecticidal properties, serves as a pivotal precursor to epipodophyllotoxin, crucial in the semisynthesis of cytostatic agents like etoposide and teniposide. The main starting compound for these anticancer medicines was podophyllotoxin, intensively isolated from Sinopodophyllum hexandrum, now listed as an endangered species due to overexploitation. Since new species are being investigated as potential sources, A. sylvestris emerges as a highly promising candidate owing to its abundant lignan content. This review summarizes the current knowledge on A. sylvestris, investigating its biological and morphological characteristics, and pharmacological properties. Emphasizing the biological activities and structure–activity relationship, this review underscores its therapeutic potential, thus encouraging further exploration and utilization of this valuable plant resource. [ABSTRACT FROM AUTHOR]

Naïve CD8+ T cells need to undergo a complex and coordinated differentiation program to gain the capacity to control virus infections. This not only involves the acquisition of effector functions, but also regulates the development of a subset of effector CD8+ T cells into long-lived and protective memory cells. Microbiotaderivedmetabolites have recently gained interest for their influence on T cells, but much remains unclear about their role in CD8+ T cell differentiation. In this study, we investigated the role of the G protein-coupled receptors (GPR)41 and GPR43 that can bind microbiota-derived short chain fatty acids (SCFAs) in CD8+ T cell priming following epicutaneous herpes simplex virus type 1 (HSV-1) infection. We found that HSV-specificCD8+ T cells in GPR41/43-deficientmicewere impaired in the antigen-elicited production of interferon-gamma (IFN-g), tumour necrosis factor-alpha (TNF-a), granzyme B and perforin, and failed to differentiate effectively into memory precursors. The defect in controlling HSV-1 at the site of infection could be restored when GPR41 and GPR43were expressed exclusively by HSV-specific CD8+ T cells. Our findings therefore highlight roles for GPR41 and GPR43 in CD8+ T cell differentiation, emphasising the importance of metabolite sensing in fine-tuning anti-viral CD8+ T cell priming. [ABSTRACT FROM AUTHOR]

Antigens from viruses or immunizations can persist or are archived in lymph node stromal cells such as lymphatic endothelial cells (LEC) and fibroblastic reticular cells (FRC). Here, we find that, during the time frame of antigen archiving, LEC apoptosis caused by a second, but unrelated, innate immune stimulus such as vaccina viral infection or CpG DNA administration resulted in cross-presentation of archived antigens and boosted memory CD8 + T cells specific to the archived antigen. In contrast to "bystander" activation associated with unrelated infections, the memory CD8 + T cells specific to the archived antigen from the immunization were significantly higher than memory CD8 + T cells of a different antigen specificity. Finally, the boosted memory CD8 + T cells resulted in increased protection against Listeria monocytogenes expressing the antigen from the immunization, but only for the duration that the antigen was archived. These findings outline an important mechanism by which lymph node stromal cell archived antigens, in addition to bystander activation, can augment memory CD8 + T cell responses during repeated inflammatory insults. [ABSTRACT FROM AUTHOR]

Inflammation is a key contributor to both the initiation and progression of tumors, and it can be triggered by genetic instability within tumors, as well as by lifestyle and dietary factors. The inflammatory response plays a critical role in the genetic and epigenetic reprogramming of tumor cells, as well as in the cells that comprise the tumor microenvironment. Cells in the microenvironment acquire a phenotype that promotes immune evasion, progression, and metastasis. We will review the mechanisms and pathways involved in the interaction between tumors, inflammation, and nutrition, the limitations of current therapies, and discuss potential future therapeutic approaches. [ABSTRACT FROM AUTHOR]

Adoptive T cell therapies have produced exceptional responses in a subset of patients with cancer. However, therapeutic efficacy can be hindered by poor T cell persistence and function1. In human T cell cancers, evolution of the disease positively selects for mutations that improve fitness of T cells in challenging situations analogous to those faced by therapeutic T cells. Therefore, we reasoned that these mutations could be co-opted to improve T cell therapies. Here we systematically screened the effects of 71 mutations from T cell neoplasms on T cell signalling, cytokine production and in vivo persistence in tumours. We identify a gene fusion, CARD11–PIK3R3, found in a CD4+ cutaneous T cell lymphoma2, that augments CARD11–BCL10–MALT1 complex signalling and anti-tumour efficacy of therapeutic T cells in several immunotherapy-refractory models in an antigen-dependent manner. Underscoring its potential to be deployed safely, CARD11–PIK3R3-expressing cells were followed up to 418 days after T cell transfer in vivo without evidence of malignant transformation. Collectively, our results indicate that exploiting naturally occurring mutations represents a promising approach to explore the extremes of T cell biology and discover how solutions derived from evolution of malignant T cells can improve a broad range of T cell therapies.A study examines the effects of mutations that occur naturally in T cell cancers, reporting that such mutations can potentially be exploited to increase the potency of T cell therapies. [ABSTRACT FROM AUTHOR]

While CD4+ T cells are a prerequisite for CD8+ T cell-mediated protection against intracellular hepatotropic pathogens, the mechanisms facilitating the transfer of CD4-help to intrahepatic CD8+ T cells are unknown. Here, we developed an experimental system to investigate cognate CD4+ and CD8+ T cell responses to a model-antigen expressed de novo in hepatocytes and reveal that after initial priming, effector CD4+ and CD8+ T cells migrate into portal tracts and peri-central vein regions of the liver where they cluster with type-1 conventional dendritic cells. These dendritic cells are locally licensed by CD4+ T cells and expand the number of CD8+ T cells in situ, resulting in larger effector and memory CD8+ T cell pools. These findings reveal that CD4+ T cells promote intrahepatic immunity by amplifying the CD8+ T cell response via peripheral licensing of hepatic type-1 conventional dendritic cells and identify intrahepatic perivascular compartments specialized in facilitating effector T cell-dendritic cell interactions. Here, English et al. show that after expanding in lymphoid tissues, CD4+ and CD8+ T cells recognising hepatic antigens migrate into specialised vascular liver areas where CD4+ T cells locally license hepatic dendritic cells and further expand CD8+ T cell numbers. [ABSTRACT FROM AUTHOR]

CD8+ T cells are classically recognized as adaptive lymphocytes based on their ability to recognize specific foreign antigens and mount memory responses. However, recent studies indicate that some antigen-inexperienced CD8+ T cells can respond to innate cytokines alone in the absence of cognate T cell receptor stimulation, a phenomenon referred to as bystander activation. Here, we demonstrate that neonatal CD8+ T cells undergo a robust and diverse program of bystander activation, which corresponds to enhanced innate-like protection against unrelated pathogens. Using a multi-omics approach, we found that the ability of neonatal CD8+ T cells to respond to innate cytokines derives from their capacity to undergo rapid chromatin remodeling, resulting in the usage of a distinct set of enhancers and transcription factors typically found in innate-like T cells. We observed that the switch between innate and adaptive functions in the CD8+ T cell compartment is mediated by changes in the abundance of distinct subsets of cells. The innate CD8+ T cell subset that predominates in early life was also present in adult mice and humans. Our findings provide support for the layered immune hypothesis and indicate that the CD8+ T cell compartment is more functionally diverse than previously thought. Editor's summary: Although T cells are primarily activated in response to antigen recognition via their T cell receptor (TCR), they can also undergo TCR-independent "bystander" activation in response to certain cytokines. Using single-cell transcriptomics and chromatin accessibility profiling, Watson et al. found that neonatal CD8+ T cells undergo a distinct and robust program of innate-like bystander activation controlled by a balance of Bach2 and AP-1 transcription factor activity. Neonatal CD8+ T cells could protect against bacterial, viral, and parasitic pathogens in a TCR-independent manner. Innate-like CD8+ T cells were also present in both adult mice and humans, indicating that multiple layers of defense may exist within the adult naïve T cell pool. —Claire Olingy [ABSTRACT FROM AUTHOR]

The protein basic helix-loop-helix family member e40 (BHLHE40) is a transcription factor recently emerged as a key regulator of host immunity to infections, autoimmune diseases and cancer. In this study, we investigated the role of Bhlhe40 in protective T cell responses to the intracellular bacterium Chlamydia in the female reproductive tract (FRT). Mice deficient in Bhlhe40 exhibited severe defects in their ability to control Chlamydia muridarum shedding from the FRT. The heightened bacterial burdens in Bhlhe40-/- mice correlated with a marked increase in IL-10-producing T regulatory type 1 (Tr1) cells and decreased polyfunctional CD4 T cells co-producing IFN-γ, IL-17A and GM-CSF. Genetic ablation of IL-10 or functional blockade of IL-10R increased CD4 T cell polyfunctionality and partially rescued the defects in bacterial control in Bhlhe40-/- mice. Using single-cell RNA sequencing coupled with TCR profiling, we detected a significant enrichment of stem-like T cell signatures in Bhlhe40-deficient CD4 T cells, whereas WT CD4 T cells were further down on the differentiation trajectory with distinct effector functions beyond IFN-γ production by Th1 cells. Altogether, we identified Bhlhe40 as a key molecular driver of CD4 T cell differentiation and polyfunctional responses in the FRT against Chlamydia. Author summary: Chlamydia is the leading cause of bacterial sexually transmitted disease worldwide. A better understanding of host immunity to this pathogen is required to develop a protective vaccine. In this study, we demonstrate that a polyfunctional CD4 T cell population capable of producing multiple cytokines (IFN-γ, IL-17A and GM-CSF) is essential for protective immunity against Chlamydia in the female reproductive tract. Moreover, we show that transcription factor Bhlhe40 acts as a key regulator that drives the differentiation of these polyfunctional CD4 T cells. Our findings provide new insights into the features of protective CD4 T cells in the host, which will guide the development of a Chlamydia vaccine. [ABSTRACT FROM AUTHOR]

Foxp3+CD4+ regulatory T (Treg) cells found within tissues regulate local immunity, inflammation, and homeostasis. Tregs in epididymal visceral adipose tissue (eVAT) are critical regulators of local and systemic inflammation and metabolism. During aging and under obesogenic conditions, eVAT Tregs undergo transcriptional and phenotypic changes and are important for containing inflammation and normalizing metabolic indices. We have employed single-cell RNA sequencing, single-cell Tra and Trb sequencing, adoptive transfers, photoconvertible mice, cellular interaction analyses, and in vitro cultures to dissect the evolving heterogeneity of eVAT Tregs with aging and obesity. Distinct Treg subtypes with distinguishable gene expression profiles and functional roles were enriched at differing ages and with differing diets. Like those in lean mice, eVAT Tregs in obese mice were not primarily recruited from the circulation but instead underwent local expansion and had a distinct and diversified T cell receptor repertoire. The different eVAT-Treg subtypes were specialized in different functions; for example, the subtypes enriched in lean, but not obese, mice suppressed adipogenesis. The existence of functionally divergent eVAT-Treg subtypes in response to obesogenic conditions presents possibilities for precision therapeutics in the context of obesity. [ABSTRACT FROM AUTHOR]

Anti-glial fibrillary acidic protein (GFAP) meningoencephalomyelitis (autoimmune GFAP astrocytopathy) is a new autoimmune central nervous system (CNS) disease diagnosable by the presence of anti-GFAP autoantibodies in the cerebrospinal fluid and presents as meningoencephalomyelitis in the majority of patients. Only few neuropathological reports are available and little is known about the pathogenic mechanisms. We performed a histopathological study of two autopsies and nine CNS biopsies of patients with anti-GFAP autoantibodies and found predominantly a lymphocytic and in one autopsy case a granulomatous inflammatory phenotype. Inflammatory infiltrates were composed of B and T cells, including tissue-resident memory T cells. Although obvious astrocytic damage was absent in the GFAP-staining, we found cytotoxic T cell-mediated reactions reflected by the presence of CD8+/perforin+/granzyme A/B+ cells, polarized towards astrocytes. MHC-class-I was upregulated in reactive astrocytes of all biopsies and two autopsies but not in healthy controls. Importantly, we observed a prominent immunoreactivity of astrocytes with the complement factor C4d. Finally, we provided insight into an early phase of GFAP autoimmunity in an autopsy of a pug dog encephalitis that was characterized by marked meningoencephalitis with selective astrocytic damage with loss of GFAP and AQP4 in the lesions. Our histopathological findings indicate that a cytotoxic T cell-mediated immune reaction is present in GFAP autoimmunity. Complement C4d deposition on astrocytes could either represent the cause or consequence of astrocytic reactivity. Selective astrocytic damage is prominent in the early phase of GFAP autoimmunity in a canine autopsy case, but mild or absent in subacute and chronic stages in human disease, probably due to the high regeneration potential of astrocytes. The lymphocytic and granulomatous phenotypes might reflect different stages of lesion development or patient-specific modifications of the immune response. Future studies will be necessary to investigate possible implications of pathological subtypes for clinical disease course and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Gene therapies have the potential to target and effectively treat a variety of diseases including cancer as well as genetic, neurological, and autoimmune disorders. Although we have made significant advances in identifying non‐viral strategies to deliver genetic cargo, certain limitations remain. In general, gene delivery is challenging for several reasons including the instabilities of nucleic acids to enzymatic and chemical degradation and the presence of restrictive biological barriers such as cell, endosomal and nuclear membranes. The emergence of lipid nanoparticles (LNPs) helped overcome many of these challenges. Despite its success, further optimization is required for LNPs to yield efficient gene delivery to extrahepatic tissues, as LNPs favor accumulation in the liver after systemic administration. In this mini‐review, we provide an overview of current preclinical approaches in that LNP surface modification was leveraged for cell and tissue targeting by conjugating aptamers, antibodies, and peptides among others. In addition to their cell uptake and efficiency‐enhancing effects, we outline the (dis‐)advantages of the different targeting moieties and commonly used conjugation strategies. [ABSTRACT FROM AUTHOR]

Malaria infection elicits both protective and pathogenic immune responses, and IL‐27 is a critical cytokine that regulate effector responses during infection. Here, we identified a critical window of CD4+ T cell responses that is targeted by IL‐27. Neutralization of IL‐27 during acute infection with Plasmodium chabaudi expanded specific CD4+ T cells, which were maintained at high levels thereafter. In the chronic phase, Plasmodium‐specific CD4+ T cells in IL‐27‐neutralized mice consisted mainly of CD127+KLRG1− and CD127−KLRG1+ subpopulations that displayed distinct cytokine production, proliferative capacity, and are maintained in a manner independent of active infection. Single‐cell RNA‐seq analysis revealed that these CD4+ T cell subsets formed independent clusters that express unique Th1‐type genes. These IL‐27‐neutralized mice exhibited enhanced cellular and humoral immune responses and protection. These findings demonstrate that IL‐27, which is produced during the acute phase of malaria infection, inhibits the development of unique Th1 memory precursor CD4+ T cells, suggesting potential implications for the development of vaccines and other strategic interventions. Synopsis: IL‐27 inhibits the generation of parasite‐specific memory CD4+ T cells in a malaria infection model. Transient blockade of IL‐27 elicits high levels of unique CD127+ and KLRG1+ memory CD4+ T cells, elevates antibody production, and enhances protective immunity against secondary infection. IL‐27 produced during the acute phase of malaria infection is inhibitory for the generation of parasite‐specific memory CD4+ T cells.Two types of unique memory CD4+ T cells are generated in the absence of IL‐27: CD127+ and KLRG1+ cells expressing high levels of Ifng and Tbx21, respectively.Memory CD4+ T cells induced in the absence of IL‐27 can be maintained in the absence of persistent malaria infection.The absence of IL‐27 during the acute phase of malaria infection generates memory immune responses that are protective against challenge infection. [ABSTRACT FROM AUTHOR]

MHC-E restricted CD8 T cells show promise in vaccine settings, but their development and specificity remain poorly understood. Here we focus on a CD8 T cell population reactive to a self-peptide (FL9) bound to mouse MHC-E (Qa-1b ) that is presented in response to loss of the MHC I processing enzyme ERAAP, termed QFL T cells. We find that mature QFL thymocytes are predominantly CD8αβ+CD4-, show signs of agonist selection, and give rise to both CD8αα and CD8αβ intraepithelial lymphocytes (IEL), as well as memory phenotype CD8αβ T cells. QFL T cells require the MHC I subunit β-2 microglobulin (β2m), but do not require Qa1b or classical MHC I for positive selection. However, QFL thymocytes do require Qa1b for agonist selection and full functionality. Our data highlight the relaxed requirements for positive selection of an MHC-E restricted T cell population and suggest a CD8αβ+CD4- pathway for development of CD8αα IELs. [ABSTRACT FROM AUTHOR]

T cell activation is initiated by the recognition of specific antigenic peptides and subsequently accomplished by complex signaling cascades. These aspects have been extensively studied for decades as pivotal factors in the establishment of adaptive immunity. However, how receptors or signaling molecules are organized in the resting state prior to encountering antigens has received less attention. Recent advancements in super-resolution microscopy techniques have revealed topographically controlled pre-formed organization of key molecules involved in antigen recognition and signal transduction on microvillar projections of T cells before activation and substantial effort has been dedicated to characterizing the topological structure of resting T cells over the past decade. This review will summarize our current understanding of how key surface receptors are pre-organized on the T-cell plasma membrane and discuss the potential role of these receptors, which are preassembled prior to ligand binding in the early activation events of T cells. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis is a major human pathogen, and new vaccines are needed to prevent transmission. Mucosal vaccination may confer protection against M. tuberculosis by stimulating tissue-resident memory (TRM) CD4+ T cells in the lungs. The chemokine receptor CXCR3 promotes lung recruitment of T cells, but its role in TRM development is unknown. This study demonstrates the recombinant influenza A virus vaccine PR8.p25, expressing the immunodominant M. tuberculosis T cell epitope p25, induces CXCR3 expression on p25-specific CD4+ T cells in the lungs so that the majority of vaccine-induced CD4+ TRM expresses CXCR3 at 6 weeks. However, CXCR3−/− mice developed equivalent antigen-specific CD4+ T cell responses to wild-type (WT) mice following PR8.p25, and surprisingly retained more p25-specific CD4+ TRM in the lungs than WT mice at 6 weeks. The adoptive transfer of CXCR3−/− and WT P25 T cells into WT mice revealed that the initial recruitment of vaccine-induced CD4+ T cells into the lungs was independent of CXCR3, but by 6 weeks, CXCR3-deficient P25 T cells, and especially CXCR3−/− TRM, were significantly reduced compared to CXCR3-sufficient P25 T cells. Therefore, although CXCR3 was not essential for CD4+ TRM recruitment or retention, it provided a competitive advantage for the induction of M. tuberculosis-specific CD4+ TRM in the lungs following pulmonary immunization. [ABSTRACT FROM AUTHOR]

Introduction: In this study, we report a novel therapeutic approach using B lymphocytes to attract islet-specific T cells in the non-obese diabetic (NOD) mouse model and prevent the development of autoimmune diabetes. Rather than using the antibody receptor of B cells, this approach utilizes their properties as antigen-presenting cells to T cells. Methods: Purified splenic B cells were treated with lipopolysaccharide, which increases regulatory B (Breg) cell function, then electroporated with mRNA encoding either chimeric MHC-I or MHC-II molecules covalently linked to antigenic peptides. Immunoregulatory functions of these engineered B cells (e-B cells) were tested by in vitro assays and in vivo co-transfer experiments with beta-cell-antigen-specific CD8+ or CD4+ T cells in NOD.Scid mice, respectively Results: The e-B cells expressing chimeric MHC-I-peptide inhibited antigen-specific CD8+ T-cell cytotoxicity in vitro. The e-B cells expressing chimeric MHC-II-peptide induced antigen-specific CD4+ T cells to express the regulatory markers, PD-1, ICOS, CTLA-4, Lag3, and Nrp1. Furthermore, e-B cells encoding the chimeric MHC-I and MHC-II peptide constructs protected NOD.Scid mice from autoimmune diabetes induced by transfer of antigen-specific CD8+ and CD4+ T cells. Discussion: MHC–peptide chimeric e-B cells interacted with pathogenic T cells, and protected the host from autoimmune diabetes, in a mouse model. Thus, we have successfully expressed MHC–peptide constructs in B cells that selectively targeted antigen-specific cells, raising the possibility that this strategy could be used to endow different protective cell types to specifically regulate/remove pathogenic cells. [ABSTRACT FROM AUTHOR]

Metabolic fitness of T cells is essential for their vitality, which is largely dependent on the behavior of the mitochondria. The nature of mitochondrial behavior in tumor-infiltrating T cells remains poorly understood. In this study, we show that mitofusin-2 (MFN2) expression is positively correlated with the prognosis of multiple cancers. Genetic ablation of Mfn2 in CD8+ T cells dampens mitochondrial metabolism and function and promotes tumor progression. In tumor-infiltrating CD8+ T cells, MFN2 enhances mitochondria–endoplasmic reticulum (ER) contact by interacting with ER-embedded Ca2+-ATPase SERCA2, facilitating the mitochondrial Ca2+ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca2+ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca2+ accumulation and apoptosis. Elevating mitochondria-ER contact by increasing MFN2 in CD8+ T cells improves the efficacy of cancer immunotherapy. Thus, we reveal a tethering-and-buffering mechanism of organelle cross-talk that regulates the metabolic fitness of tumor-infiltrating CD8+ T cells and highlights the therapeutic potential of enhancing MFN2 expression to optimize T cell function. Editor's summary: Organelle cross-talk plays a fundamental role in cell biology, but how this cross-talk controls tumor-infiltrating CD8+ T cells (TILs) is not understood. Yang et al. investigate the role of MFN2 in CD8+ TILs, identifying that mitochondrial interaction with the endoplasmic reticulum (ER) is required for metabolic fitness and antitumor activity. Through interaction with SERCA2 on the ER, MFN2 was required for mitochondria-ER contact and Ca2+ homeostasis. MFN2 expression was associated with better survival in patients with cancer, and promoting MFN2 expression in CD8+ T cells improved response to immune checkpoint blockade in mice. Together, these findings identify a critical role for MFN2 in regulating the metabolism, function, and survival of CD8+ T cells and suggest that boosting MFN2 expression is an attractive avenue for improving immunotherapy. —Hannah Isles [ABSTRACT FROM AUTHOR]

Rising obesity levels, worldwide, are resulting in substantial increases in cardiovascular disease, diabetes, kidney disease, musculoskeletal disorders, and certain cancers, and obesity-associated illnesses are estimated to cause ∼4 million deaths worldwide per year. A common theme in this disease epidemic is the chronic systemic inflammation that accompanies obesity. CD4+ Foxp3+ regulatory T cells residing in visceral adipose tissues (VAT Tregs) are a unique immune cell population that play essential functions in restricting obesity-associated systemic inflammation through regulation of adipose tissue homeostasis. The distinct transcriptional program that defines VAT Tregs has been described, but directly linking VAT Treg differentiation and function to improving insulin sensitivity has proven more complex. Here we review new findings which have clarified how VAT Tregs differentiate, and how distinct VAT Treg subsets regulate VAT homeostasis, energy expenditure, and insulin sensitivity. [ABSTRACT FROM AUTHOR]

Although significant strides have been made in the understanding of pulmonary immunology, much work remains to be done to comprehensively explain coordinated immune responses in the lung. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic only served to highlight the inadequacy of current models of host–pathogen interactions and reinforced the need for current and future generations of immunologists to unravel complex biological questions. As part of that effort, the 64th Annual Thomas L. Petty Aspen Lung Conference was themed “Bridging the Gap between Innate and Adaptive Immunity in the Lung” and featured exciting work from renowned immunologists. This report summarizes the proceedings of the 2022 Aspen Lung Conference, which was convened to discuss the roles played by innate and adaptive immunity in disease pathogenesis, evaluate the interface between the innate and adaptive immune responses, assess the role of adaptive immunity in the development of autoimmunity and autoimmune lung disease, discuss lessons learned from immunologic cancer treatments and approaches, and define new paradigms to harness the immune system to prevent and treat lung diseases. [ABSTRACT FROM AUTHOR]

Recent advances in neoantigen research have accelerated the development of tumor immunotherapies, including adoptive cell therapies (ACTs), cancer vaccines and antibody-based therapies, particularly for solid tumors. With the development of next-generation sequencing and bioinformatics technology, the rapid identification and prediction of tumor-specific antigens (TSAs) has become possible. Compared with tumor-associated antigens (TAAs), highly immunogenic TSAs provide new targets for personalized tumor immunotherapy and can be used as prospective indicators for predicting tumor patient survival, prognosis, and immune checkpoint blockade response. Here, the identification and characterization of neoantigens and the clinical application of neoantigen-based TCR-T immunotherapy strategies are summarized, and the current status, inherent challenges, and clinical translational potential of these strategies are discussed. Key points: 1) Established the computational process and platform of neoantigen prediction, and comprehensive prediction and screening of tumor specific neoantigens. 2) Rapid identification of neoantigen-specific TCRs for personalized engineered TCR-T cell therapy. 3) Classification and characteristics of tumor specific neoantigen-based therapy, and combined antitumor strategies. 4) The current status, inherent challenges, and clinical translational potential of TCR-T therapy. [ABSTRACT FROM AUTHOR]

The healthy human cornea is a uniquely transparent sensory tissue where immune responses are tightly controlled to preserve vision. The cornea contains immune cells that are widely presumed to be intraepithelial dendritic cells (DCs). Corneal immune cells have diverse cellular morphologies and morphological alterations are used as a marker of inflammation and injury. Based on our imaging of corneal T cells in mice, we hypothesized that many human corneal immune cells commonly defined as DCs are intraepithelial lymphocytes (IELs). To investigate this, we developed functional in vivo confocal microscopy (Fun-IVCM) to investigate cell dynamics in the human corneal epithelium and stroma. We show that many immune cells resident in the healthy human cornea are T cells. These corneal IELs are characterized by rapid, persistent motility and interact with corneal DCs and sensory nerves. Imaging deeper into the corneal stroma, we show that crawling macrophages and rare motile T cells patrol the tissue. Furthermore, we identify altered immune cell behaviors in response to short-term contact lens wear (acute inflammatory stimulus), as well as in individuals with allergy (chronic inflammatory stimulus) that was modulated by therapeutic intervention. These findings redefine current understanding of immune cell subsets in the human cornea and reveal how resident corneal immune cells respond and adapt to chronic and acute stimuli. [ABSTRACT FROM AUTHOR]

Autoreactive encephalitogenic T cells exist in the healthy immune repertoire but need a trigger to induce CNS inflammation. The underlying mechanisms remain elusive, whereby microbiota were shown to be involved in the manifestation of CNS autoimmunity. Here, we used intravital imaging to explore how microbiota affect the T cells as trigger of CNS inflammation. Encephalitogenic CD4+ T cells transduced with the calcium-sensing protein Twitch-2B showed calcium signaling with higher frequency than polyclonal T cells in the small intestinal lamina propria (LP) but not in Peyer’s patches. Interestingly, nonencephalitogenic T cells specific for OVA and LCMV also showed calcium signaling in the LP, indicating a general stimulating effect of microbiota. The observed calcium signaling was microbiota and MHC class II dependent as it was significantly reduced in germfree animals and after administration of anti-MHC class II antibody, respectively. As a consequence of T cell stimulation in the small intestine, the encephalitogenic T cells start expressing Th17-axis genes. Finally, we show the migration of CD4+ T cells from the small intestine into the CNS. In summary, our direct in vivo visualization revealed that microbiota induced T cell activation in the LP, which directed T cells to adopt a Th17-like phenotype as a trigger of CNS inflammation. [ABSTRACT FROM AUTHOR]

The use of therapeutic proteins and peptides is of great interest for the treatment of many diseases, and advances in nanotechnology offer a path toward their stable delivery via preferred routes of administration. In this study, we sought to design and formulate a nanostructured lipid carrier (NLC) containing a nominal antigen (insulin peptide) for oral delivery. We utilized the design of experiments (DOE) statistical method to determine the dependencies of formulation variables on physicochemical particle characteristics including particle size, polydispersity (PDI), melting point, and latent heat of melting. The particles were determined to be non‐toxic in vitro, readily taken up by primary immune cells, and found to accumulate in regional lymph nodes following oral administration. We believe that this platform technology could be broadly useful for the treatment of autoimmune diseases by supporting the development of oral delivery‐based antigen specific immunotherapies. [ABSTRACT FROM AUTHOR]

Summary: Memory T cells form an essential part of immunological memory, which can last for years or even a lifetime. Much experimental work has shown that the individual cells that make up the memory T‐cell pool are in fact relatively short‐lived. Memory T cells isolated from the blood of humans, or the lymph nodes and spleen of mice, live about 5–10 fold shorter than naive T cells, and much shorter than the immunological memory they convey. The commonly accepted view is, therefore, that long‐term T‐cell memory is maintained dynamically rather than by long‐lived cells. This view is largely based on memory T cells in the circulation, identified using rather broad phenotypic markers, and on research in mice living in overly clean conditions. We wondered to what extent there may be heterogeneity in the dynamics and lifespans of memory T cells. We here review what is currently known about the dynamics of memory T cells in different memory subsets, locations in the body and conditions of microbial exposure, and discuss how this may be related to immunometabolism and how this knowledge can be used in various clinical settings. [ABSTRACT FROM AUTHOR]

Various autoimmune responses increase with age, but the underlying mechanism is not clear. In this study, we used CD4+ T cells expressing a transgenic T cell receptor specific for desmoglein 3 (Dsg3), which is the target antigen of the autoimmune bullous disease pemphigus vulgaris, to examine how peripheral immunological tolerance against pathogenic autoreactive CD4+ T cells changes with age. Dsg3-specific T cells were deleted within 14 days after adoptive transfer into young mice (8 weeks old), while they escaped deletion when transferred into older mice over 42 weeks old. Dsg3-specific T cells produced higher levels of the proinflammatory cytokine IFN-γ in aged mice than in young mice. In addition, the expression levels of both OX40 and Birc5, which are important for cell survival in T cell clonal proliferation, were higher in aged than in young mice. The dysfunction in suppressing proinflammatory cytokine secretion and Birc5 upregulation in Dsg3-specific autoreactive T cells may reflect an aspect of the preliminary steps in autoimmune disease development in the aged population. Understanding this mechanism may lead to better risk evaluation of autoimmune disease development and to onset prevention. [ABSTRACT FROM AUTHOR]

Numerous alterations in CD8+ T cells contribute to impaired immune responses in elderly individuals. However, the discrimination between cell‐intrinsic dysfunctions and microenvironmental changes is challenging. TCR transgenic OT‐I mice are utilized to investigate CD8+ T‐cell immunity, but their immunodeficient phenotype hampers their use especially in aging. Here, we demonstrate that using a heterozygous OT‐I model minimizes the current limitations and provides a valuable tool to assess antigen‐specific T‐cell responses even at old age. We analyzed phenotypic and functional characteristics of CD8+ T cells from OT‐I+/+ and OT‐I+/− mice to prove the applicability of the heterozygous system. Our data reveal that OVA‐activated CD8+ T cells from adult OT‐I+/− mice proliferate, differentiate, and exert cytolytic activity equally to their homozygous counterparts. Moreover, common age‐related alterations in CD8+ T cells, including naive T‐cell deterioration and decreased proliferative capacity, also occur in elderly OT‐I+/− mice, indicating the wide range of applications for in vivo and in vitro aging studies. We used the OT‐I+/− model to investigate cell‐intrinsic alterations affecting the cytotoxic behavior of aged CD8+ T cells after antigen‐specific in vitro activation. Time‐resolved analysis of antigen‐directed target cell lysis confirmed previous observations that the cytotoxic capacity of CD8+ T cells increases with age. Surprisingly, detailed single cell analysis revealed that transcriptional upregulation of perforin in aged CD8+ T cells shifts the mode of target cell death from granzyme‐mediated apoptosis to rapid induction of necrosis. This unexpected capability might be beneficial or detrimental for the aging host and requires detailed evaluation. [ABSTRACT FROM AUTHOR]

In severe respiratory virus infections, including influenza, an exaggerated host immune response has been linked to the severe disease and death. Control of the overwhelming immune response is thus essential. Efforts with broad‐spectrum immunosuppressive agents such as steroids are disappointing. A better understanding of host immune response using animal experimental system is required to avoid undesired outcome of experimental manipulation. Following severe influenza virus infection in influenza hemagglutinin antigen‐specific transgenic mouse experimental model, step‐wise evolving cells from a pool of naïve hemagglutinin‐specific CD4+ T cells were studied for phenotypic, genomic, and functional characterization in vivo. Naïve CD4+ T cells respond with Th1 commitment in the absolute majority. They first develop into LAG‐3MedIFN‐γ‐secreting Th1 effectors and then evolve into LAG‐3HighIFN‐γ‐not‐secreting regulators with increasing LAG‐3 expression upon continuous activation and cell division. The LAG‐3MedIFN‐γ‐secreting effectors contribute to inflammation, boost inflammatory response of cognate antigen‐specific CD8+ T cells, and aggravate the disease despite facilitated virus clearance. In contrast, LAG‐3High regulators do not contribute to inflammation, suppress CD8+ T cell inflammatory response, alleviate lung pathology, and ameliorate the disease with preserved virus clearance. Moderated CD8+ T cells retain proliferative capacity, and persist beyond virus clearance. Such moderation is distinct from Foxp‐3+ regulator‐mediated suppression, which suppresses proliferative and inflammatory responses of the CD8+ T cells and impairs virus clearance with inflammation alleviation. Origin of regulatory from the effector cells of LAG‐3‐marked Th1 immunity alleviates lung inflammation without impairment of virus eradication. [ABSTRACT FROM AUTHOR]

Excessive inflammation is a postulated cause of severe disease and death in respiratory virus infections. In response to severe influenza virus infection, adoptively transferred naïve hemagglutinin-specific CD4+ T cells from CD4+ TCR-transgenic 6.5 mice drive an IFN-γ-producing Th1 response in wild-type mice. It helps in virus clearance but also causes collateral damage and disease aggravation. The donor 6.5 mice have all the CD4+ T cells with TCR specificity toward influenza hemagglutinin. Still, the infected 6.5 mice do not suffer from robust inflammation and grave outcome. The initial Th1 response wanes with time, and a prominent Th17 response of recent thymic emigrants alleviates inflammation and bestows protection in 6.5 mice. Our results suggest that viral neuraminidase-activated TGF-β of the Th1 cells guides the Th17 evolution, and IL-17 signaling through the non-canonical IL-17 receptor EGFR activates the scaffold protein TRAF4 more than TRAF6 during alleviation of lung inflammation in severe influenza. Adaptive transfer experiments using an influenza hemagglutinin antigen-specific mouse model suggest that viral neuraminidase-activated TGF-β from Th1 cells guides Th17 evolution to promote protection from lung inflammation in severe influenza. [ABSTRACT FROM AUTHOR]

Post kala‐azar dermal leishmaniasis (PKDL), a sequel of apparently cured visceral leishmaniasis (VL) presents with papulonodular (polymorphic) or hypopigmented lesions (macular) and is the proposed disease reservoir. As hypopigmentation appears consistently in PKDL, especially the macular form, this study aimed to delineate immune factors that singly or in combination could contribute towards this hypopigmentation. At lesional sites, the presence of melanocytes and CD8+ T‐cells was assessed by immunohistochemistry and mRNA expression of melanogenic markers (tyrosinase, tyrosinase‐related protein‐1 and MITF) by droplet digital PCR, while plasma levels of cytokines and chemokines were measured by a multiplex assay. In comparison with skin from healthy individuals, macular PKDL demonstrated a near total absence of Melan‐A+ cells at dermal sites, while the polymorphic cases demonstrated a 3.2‐fold decrease, along with a dramatic reduction in the expression of key enzymes related to the melanogenesis signalling pathway in both forms. The levels of circulating IFN‐γ, IL‐6, IL‐2, IL‐1β, TNF‐α and IFN‐γ‐inducible chemokines (CXCL9/10/11) were elevated and was accompanied by an increased lesional infiltration of CD8+ T‐cells. The proportion of CD8+ T‐cells correlated strongly with plasma levels of IFN‐γ (r = 0.8), IL‐6 (r = 0.9, p < 0.05), IL‐2 (r = 0.7), TNF‐α (r = 0.9, p < 0.05) and IL‐1β (r = 0.7), as also with CXCL9 (r = 0.5) and CXCL10 (r = 0.6). Taken together, the absence/reduction in Melan‐A suggested hypopigmentation in PKDL was associated with the destruction of melanocytes, following the impairment of the melanogenesis pathway. Furthermore, the presence of CD8+ T‐cells and an enhanced IFN‐γ‐associated immune milieu suggested the generation of a pro‐inflammatory landscape that facilitated melanocyte dysfunction/destruction. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections are highly prevalent in the human population and produce mild to life-threatening diseases. These viruses interfere with the function and viability of dendritic cells (DCs), which are professional antigen-presenting cells that initiate and regulate the host's antiviral immune responses. Heme oxygenase-1 (HO-1) is an inducible host enzyme with reported antiviral activity against HSVs in epithelial cells and neurons. Here, we sought to assess whether HO-1 modulates the function and viability of DCs upon infection with HSV-1 or HSV-2. We found that the stimulation of HO-1 expression in HSV-inoculated DCs significantly recovered the viability of these cells and hampered viral egress. Furthermore, HSV-infected DCs stimulated to express HO-1 promoted the expression of anti-inflammatory molecules, such as PDL-1 and IL-10, and the activation of virus-specific CD4+ T cells with regulatory (Treg), Th17 and Treg/Th17 phenotypes. Moreover, HSV-infected DCs stimulated to express HO-1 and then transferred into mice, promoted the activation of virus-specific T cells and improved the outcome of HSV-1 skin infection. These findings suggest that stimulation of HO-1 expression in DCs limits the deleterious effects of HSVs over these cells and induces a favorable virus-specific immune response in the skin against HSV-1. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T‐cell therapy is an immunotherapy approach that has played a tremendous role in the battle against cancer for years. Since the CAR T lymphocytes are unrestricted‐major histocompatibility complex T lymphocytes, they could identify more targets than natural T cells, resulting in practical and widespread functions. The good prospects of CAR T‐cell therapy in oncology can be additionally applied to treat other diseases such as autoimmune and infectious diseases. CAR‐T cell‐derived immunotherapy for autoimmune disorders can be allocated to CAR‐Tregs and chimeric autoantibody receptor T cells. Other generations of CARs target human immunodeficiency virus (HIV) proteins. In this review, we summarize CAR‐T cell therapies in autoimmune disorders and HIV infection. [ABSTRACT FROM AUTHOR]

Vitiligo is a common primary, limited or generalized skin depigmentation disorder. Its pathogenesis is complex, multifactorial and unclear. For this reason, few animal models can simulate the onset of vitiligo, and studies of drug interventions are limited. Studies have found that there may be a pathophysiological connection between mental factors and the development of vitiligo. At present, the construction methods of the vitiligo model mainly include chemical induction and autoimmune induction against melanocytes. Mental factors are not taken into account in existing models. Therefore, in this study, mental inducement was added to the monobenzone (MBEH)-induced vitiligo model. We determined that chronic unpredictable mild stress (CUMS) inhibited the melanogenesis of skin. MBEH inhibited melanin production without affecting the behavioral state of mice, but mice in the MBEH combined with CUMS (MC) group were depressed and demonstrated increased depigmentation of the skin. Further analysis of metabolic differences showed that all three models altered the metabolic profile of the skin. In summary, we successfully constructed a vitiligo mouse model induced by MBEH combined with CUMS, which may be better used in the evaluation and study of vitiligo drugs. [ABSTRACT FROM AUTHOR]

Adoptive cell transfer (ACT) therapies have gained renewed interest in the field of immunotherapy following the advent of chimeric antigen receptor (CAR) technology. This immunological breakthrough requires immune cell engineering with an artificial surface protein receptor for antigen‐specific recognition coupled to an intracellular protein domain for cell activating functions. CAR‐based ACT has successfully solved some hematological malignancies, and it is expected that other tumors may soon benefit from this approach. However, the potential of CAR technology is such that other immune‐mediated disorders are beginning to profit from it. This review will focus on CAR‐based ACT therapeutic areas other than oncology such as infection, allergy, autoimmunity, transplantation, and fibrotic repair. Herein, we discuss the results and limitations of preclinical and clinical studies in that regard. [ABSTRACT FROM AUTHOR]

During chronic infections, a distinct physiological condition named "exhaustion" arises that is associated with the dysfunctionality in immune cells and their eventual removal from the environment, which evidently help the progress of infection or tumors in human or animal bodies. This state of immune cells could be under the control of different elements such as the antigen load, help from inhibitory cells, lack of costimulatory signals and etc. Exhaustion that has been found in different immune system cells, is usually accompanied by impaired effector function and proliferation of immune cells, poor memory recall, upregulation of inhibitory molecules, compromised metabolism and altered transcription program, and is considered a reversible process, unlike other physiological states like anergy or senescence, organized through the blockage of several factors. Although the emergence of these cells in viral infections and cancer is an undesirable event, the importance of the presence of exhausted cells in autoimmune diseases and organ transplantation is highlighted as a positive change. In this review, we aimed to determine the occurrence of this process in different immune cells, the characteristics obtained by these cells, effective and primitive factors on exhaustion, metabolic and transcriptional cell changes, and the use of these cells in autoimmune diseases and organ transplantation. [ABSTRACT FROM AUTHOR]

T cell activation and effector functions are determined by the affinity of the interaction between T cell receptor (TCR) and its antigenic peptide MHC (pMHC) ligand. A better understanding of the quantitative aspects of TCR‐pMHC affinity‐dependent T cell activation is critical for the development of new immunotherapeutic strategies. However, the role of TCR‐pMHC affinity in regulating the kinetics of CD8+ T cell commitment to proliferation and differentiation is unknown. Here, we show that the stronger the TCR‐pMHC affinity, the shorter the time of T cell‐APC co‐culture required to commit CD8+ T cells to proliferation. The time threshold for T cell cytokine production is much lower than that for cell proliferation. There is a strong correlation between affinity‐dependent differences in AKT phosphorylation and T cell proliferation. The cytokine IL‐15 increases the poor proliferation of T cells stimulated with low affinity pMHC, suggesting that pro‐inflammatory cytokines can override the affinity‐dependent features of T cell proliferation. Synopsis: High affinity TCR stimulation needs shorter time than low affinity to commit CD8+ T cells to proliferation, strongly correlated with AKT phosphorylation. IL‐15 reduces the time threshold for commitment by low affinity stimuli. The time of commitment to proliferation is longer for T cells stimulated with low affinity ligands.Effector cytokine production is dependent neither on ligand affinity nor on duration of T cell exposure to APC.There is a strong correlation between affinity‐dependent differences in AKT phosphorylation and T cell proliferation.The presence of pro‐inflammatory cytokines could override affinity‐dependent features of T cell signaling for proliferation. [ABSTRACT FROM AUTHOR]