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Materno-fetal immunity possesses specialized characteristics to ensure pathogen clearance while maintaining tolerance to the semiallogeneic fetus. Most of our understanding on human materno-fetal immunity is based on conventional rodent models that may not precisely represent human immunological processes owing to the huge evolutionary divergence. Herein, we developed a pregnant human immune system (HIS) mouse model through busulfan preconditioning, which hosts multilineage human immune subset reconstitution at the materno-fetal interface. Human materno-fetal immunity exhibits a tolerogenic feature at the midgestation stage (embryonic day [E] 14.5), and human immune regulatory subsets were detected in the decidua. However, the immune system switches to an inflammatory profile at the late gestation stage (E19). A cell-cell interaction network contributing to the alternations in the human materno-fetal immune atmosphere was revealed based on single-cell RNA-Seq analysis, wherein human macrophages played crucial roles by secreting several immune regulatory mediators. Furthermore, depletion of Treg cells at E2.5 and E5.5 resulted in severe inflammation and fetus rejection. Collectively, these results demonstrate that the pregnant HIS mouse model permits the development of functional human materno-fetal immunity and offers a tool for human materno-fetal immunity investigation to facilitate drug discovery for reproductive disorders.

After transplantation, Th1-mediated immune rejection is the predominant cause of graft failure. Th1 cell sensitization occurs through complex and context-dependent interaction among antigen-presenting cell subsets, particularly CD11b+ DCs (DC2) and CD103+ DCs (DC1). This interaction necessitates further investigation in the context of transplant immunity. We used well-established preclinical models of corneal transplantation and identified distinct roles of migratory CD103+ DC1 in influencing the outcomes of the grafted tissue. In recipients with uninflamed corneal beds, migratory CD103+ DC1 demonstrate a tolerogenic phenotype that modulates the immunogenic capacity of CD11b+ DC2 primarily mediated by IL-10, suppressing alloreactive CD4+ Th1 cells via the PD-L1/PD-1 pathway and enhancing Treg-mediated tolerance via αvβ8 integrin-activated TGF-β1, thus facilitating graft survival. Conversely, in recipients with inflamed and vascularized corneal beds, IFN-γ produced by CD4+ Th1 cells induced migratory CD103+ DC1 to adopt an immunostimulatory phenotype, characterized by the downregulation of regulatory markers, including αvβ8 integrin and IL-10, and the upregulation of IL-12 and costimulatory molecules CD80/86, resulting in graft failure. The adoptive transfer of ex vivo induced tolerogenic CD103+ DC1 (iDC1) effectively inhibited Th1 polarization and preserved the tolerogenic phenotype of their physiological counterparts. Collectively, our findings underscore the essential role played by CD103+ DC1 in modulating host alloimmune responses.

Purpose of Review: Recognition of the importance of innate lymphoid cells (ILCs) in the immune mechanisms of food allergy has grown in recent years. This review summarizes recent findings of ILCs in immunoglobulin E (IgE)-mediated food allergy. New research on ILCs in the context of the microbiome and other atopic diseases are also considered with respect to how they can inform understanding of the role of ILCs in food allergy., Recent Findings: ILCs can mediate allergic and tolerogenic responses through multiple pathways. A novel subset of interleukin (IL)-10 producing ILC2s are associated with tolerance following immunotherapy to grass pollen, house dust mite allergy and lipid transfer protein allergy. ILC2s can drive food allergen-specific T cell responses in an antigen-specific manner. A memory subset of ILC2s has been identified through studies of other atopic diseases and is associated with effectiveness of response to therapy., Summary: The role of ILCs in food allergy and oral tolerance is relatively understudied compared to other diseases. ILCs can modulate immune responses through several mechanisms, and it is likely that these are of importance in the context of food allergy. Better understanding of theses pathways may help to answer fundamental questions regarding the development of food allergy and lead to novel therapeutic targets and treatment., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Intestinal macrophages play a key role in regulating immune tolerance in the gut. In this issue of Immunity, Mertens et al. uncover a mechanism for the establishment of memory in macrophage tolerance in the gut involving a bistable metabolic switch in macrophages and an intercellular positive feedback between macrophages and intestinal epithelial cells (IECs)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bats are natural reservoirs for zoonotic pathogens, yet the determinants of microbial persistence as well as the specific functionality of their immune system remain largely enigmatic. Their propensity to harbor viruses lethal to humans and/or livestock, mostly in absence of clinical disease, makes bats stand out among mammals. Defending against pathogens relies on avoidance, resistance, and/or tolerance strategies. In bats, disease tolerance has recently gained increasing attention as a prevailing host defense paradigm. We here summarize the current knowledge on immune responses in bats in the context of infection with zoonotic agents and discuss concepts related to disease tolerance. Acknowledging the wide diversity of bats, the broad spectrum of bat-associated microbial species, and immune-related knowledge gaps, we identify research priorities necessary to provide evidence-based proofs for disease tolerance in bats. Since disease tolerance relies on networks of biological processes, we emphasize that investigations beyond the immune system, using novel technologies and computational biology, could jointly advance our knowledge about mechanisms conferring bats reservoir abilities. Although disease tolerance may not be the "one fit all" defense strategy, deciphering disease tolerance in bats could translate into novel therapies and inform prevention of spillover infections to humans and livestock., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Identifying tumor-mediated mechanisms that impair immunity is instrumental for the design of new cancer therapies. Regulatory T cells (Tregs) are a key component of cancer-derived immune suppression; however, these lymphocytes are necessary to prevent systemic autoimmunity in mice and humans, and thus, direct targeting of Tregs is not a clinical option for cancer patients. We have previously demonstrated that excising transcription factor Kruppel-like factor 2 ( Klf2 ) within the T cell lineage blocks the generation of peripheral-derived Tregs (pTregs) without impairing production of thymic-derived Tregs. Using this mouse model, we have now demonstrated that eliminating pTregs is sufficient to delay/prevent tumor malignancy without causing autoimmunity. Cancer-bearing mice that expressed KLF2 converted tumor-specific CD4 + T cells into pTregs, which accumulated in secondary lymphoid organs and impaired further T cell effector activity. In contrast, pTreg-deficient mice retained cancer-specific immunity, including improved T cell infiltration into "cold" tumors, reduced T cell exhaustion in tumor beds, restricted generation of tumor-associated myeloid-derived suppressor cells, and the continued production of circulating effector T cells that arose in a cancer-dependent manner. Results indicate that tumor-specific pTregs are critical for early stages of cancer progression and blocking the generation of these inhibitory lymphocytes safely delays/prevents malignancy in preclinical models of melanoma and prostate cancer., Competing Interests: Competing interests statement:The authors declare no competing interest.

Failures in peripheral immune tolerance mechanisms create a permissive environment for autoimmune diabetes initiation and disease progression. Biomarker analyses provide tools that allow recognition of this loss of tolerance, reflecting a serial acquisition of pathogenic characteristics causally linked to islet β-cell dysfunction and death. Autoimmune effector cell activation and expansion, ineffective immune regulation, and tissue response to injury during active disease each represent challenges to homeostasis; however, they also represent targets for therapeutic intervention, with the potential for restoration of tolerance. Limited success in recent clinical trials demonstrates that tolerance in type 1 diabetes (T1D) is achievable, but currently occurs in few subjects and is not durable in most. Combining therapeutic agents to rebuild multiple immune components to restore tolerance, particularly addressing both effector and regulatory T-cell dysfunction, is needed., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

Adaptive immune cell function is regulated by a highly diverse receptor recombined from variable germline-encoded segments that can recognize an almost unlimited array of epitopes. While this diversity enables the recognition of any pathogen, it also poses a risk of self-recognition, leading to autoimmunity. Many layers of regulation are present during both the generation and activation of B cells to prevent this phenomenon, although they are evidently imperfect. In recent years, our ability to analyze immune repertoires at scale has drastically increased, both through advances in sequencing and single-cell analyses. Here, we review the current knowledge on B cell repertoire analyses, focusing on their implication for autoimmunity. These studies demonstrate that a failure of tolerance occurs at multiple independent checkpoints in different autoimmune contexts, particularly during B cell maturation, plasmablast differentiation, and within germinal centers. These failures are marked by distinct repertoire features that may be used to identify disease- or patient-specific therapeutic approaches., (© 2024 Deguine and Xavier.)

Atherosclerotic cardiovascular disease (ASCVD) is a chronic inflammatory disease of the arterial walls and is characterized by the accumulation of lipoproteins that are insufficiently cleared by phagocytes. Following the initiation of atherosclerosis, the pathological progression is accelerated by engagement of the adaptive immune system. Atherosclerosis triggers the breakdown of tolerance to self-components. This loss of tolerance is reflected in defective expression of immune checkpoint molecules, dysfunctional antigen presentation, and aberrations in T cell populations - most notably in regulatory T (T reg ) cells - and in the production of autoantibodies. The breakdown of tolerance to self-proteins that is observed in ASCVD may be linked to the conversion of T reg cells to 'exT reg ' cells because many T reg cells in ASCVD express T cell receptors that are specific for self-epitopes. Alternatively, or in addition, breakdown of tolerance may trigger the activation of naive T cells, resulting in the clonal expansion of T cell populations with pro-inflammatory and cytotoxic effector phenotypes. In this Perspective, we review the evidence that atherosclerosis is associated with a breakdown of tolerance to self-antigens, discuss possible immunological mechanisms and identify knowledge gaps to map out future research. Rational approaches aimed at re-establishing immune tolerance may become game changers in treating ASCVD and in preventing its downstream sequelae, which include heart attacks and strokes., (© 2024. Springer Nature Limited.)

Despite the success of immunotherapy in treating hepatocellular carcinoma (HCC), HCC remains a severe threat to health. Here, a crucial transcription factor, SOX12, is revealed that induces the immunosuppression of liver tumor microenvironment. Overexpressing SOX12 in HCC syngeneic models increases intratumoral regulatory T-cell (Treg) infiltration, decreases CD8 + T-cell infiltration, and hastens HCC metastasis. Hepatocyte-specific SOX12 knockout attenuates DEN/CCl 4 -induced HCC progression and metastasis, whereas hepatocyte-specific SOX12 knock-in accelerates these effects. Mechanistically, SOX12 transcriptionally activates C-C motif chemokine ligand 22 (CCL22) expression to promote the recruitment and suppressive activity of Tregs. Moreover, SOX12 transcriptionally upregulates CD274 expression to suppress CD8 + T-cell infiltration. Either knockdown of CCL22 or PD-L1 dampens SOX12-mediated HCC metastasis. Blocking of CC chemokine receptor 4 (CCR4), a receptor for CCL22, by inhibitor C-021 or Treg-specific knockout of CCR4 inhibits SOX12-mediated HCC metastasis. Transforming growth factor-β1 (TGF-β1)/TGFβR1-Smad2/3/4 is identified as a key upstream signaling for SOX12 overexpression in HCC cells. Combining C-021 or TGFβR1 inhibitor galunisertib with anti-PD-L1 exhibits an enhanced antitumor effect in two HCC models. Collectively, the findings demonstrate that SOX12 contributes to HCC immunosuppression through the CCL22/CCR4-Treg and PD-L1-CD8 + T axes. Blocking of CCR4 or TGFβR1 improves the efficacy of anti-PD-L1 in SOX12-mediated HCC., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Highly inflamed and neovascularized corneal graft beds are known as high-risk (HR) environments for transplant survival. One of the primary factors leading to this rejection is reduction in the suppressive function of regulatory T cells (Treg). Our results show that myeloid-derived suppressor cells (MDSC) counteract interleukin-6-mediated Treg dysfunction by expressing interleukin-10. Additionally, MDSC maintain forkhead box P3 stability and their ability to suppress IFN-γ + Th1 cells. Administering MDSC to HR corneal transplant recipients demonstrates prolonged graft survival via promotion of Treg while concurrently suppressing IFN-γ + Th1 cells. Moreover, MDSC-mediated donor-specific immune tolerance leads to long-term corneal graft survival as evidenced by the higher survival rate or delayed survival of a second-party C57BL/7 (B6) graft compared to those of third-party C3H grafts observed in contralateral low-risk or HR corneal transplantation of BALB/c recipient mice, respectively. Our study provides compelling preliminary evidence demonstrating the effectiveness of MDSC in preventing Treg dysfunction, significantly improving graft survival in HR corneal transplantation, and showing promising potential for immune tolerance induction., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

The skin is the largest immunologic organ in the body and contains immune cells that play a role in both food allergen sensitization and desensitization. The dual allergen exposure hypothesis posits that sensitization to food allergens may occur with cutaneous exposure on inflamed skin, eg, atopic dermatitis, but early oral consumption generally leads to tolerance. However, only one-third of children with atopic dermatitis develop a food allergy, suggesting that there is a more complex mechanism for allergen sensitization. Emerging evidence suggests that the outcome of cutaneous allergen exposure is context-dependent and largely influenced by the state of the skin barrier with healthy skin promoting natural tolerance. Current research supports the ability to induce desensitization through repeated application of allergens to the skin, known as epicutaneous immunotherapy. Preclinical research with an occlusive patch has demonstrated a significantly reduced T-helper cell type 2-driven immunologic response when applied to intact, uninflamed skin and induction of a unique population of regulatory T cells that express a broader range of homing receptors, which may be able to maintain sustained protection. In clinical studies of children aged 1 through 11 years with a peanut allergy, epicutaneous immunotherapy with an occlusive patch led to significant desensitization with no major differences in efficacy or safety between children with and without atopic dermatitis. These data begin to answer the conundrum of how allergens that are applied to the skin can lead to both sensitization and desensitization, and future studies should enable us to optimize the power of the skin as a complex immunologic organ to treat allergic, autoimmune, and autoinflammatory disorders., Competing Interests: Disclosures H.A.S. reports receiving funding from the National Institute of Allergy and Infectious Diseases; consulting fees from DBV Technologies, S.A., N-Fold Therapeutics, LLC, and Siolta, Inc; and stock options from DBV Technologies and N-Fold Therapeutics., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Dendritic cells are critical inducers of adaptive anti-tumor immunity. However, their maturation, activation, and migration are often compromised in the tumor microenvironment. In this issue, You et al. demonstrate a novel axis of suppression of dendritic cell function mediated by interaction with regulatory T cells in perilymphatic niches., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chronic hepatitis B (CHB) virus infection, which can be divided into immune-tolerant (IT), immune-active (IA), inactive carrier (IC) phases, and HBeAg-negative hepatitis (ENEG), can induce liver cirrhosis and eventually hepatocellular carcinoma (HCC). CD3 + CD56 + NKT-like cells play an important role in antiviral immune response. However, the mechanism of NKT-like cells to mediate immune tolerance remains largely elusive. In this study, we observed circulating NKT-like cells from IC and IT CHB patients were phenotypically and functionally impaired, manifested by increased expression of inhibitory receptor TIGIT and decreased capacity of secreting antiviral cytokines. Besides, TIGIT + NKT-like cells of IC and IT CHB patients expressed lower levels of cytotoxic cytokines than the TIGIT - subset. Furthermore, increased expression of CD155, the ligand of TIGIT, on plasmacytoid dendritic cells (pDCs) was detected in IC and IT CHB patients. Importantly, the co-culture of NKT-like cells and pDCs showed that NKT-like cells restored their antiviral ability after TIGIT blockade upon HBV peptide stimulation in IC and IT CHB patients. In conclusion, our findings suggest that the TIGIT pathway may mediate immune tolerance in IT CHB patients and lead to functional impairment in IC patients, indicating that TIGIT may be a potential therapeutic checkpoint for immunotherapy of CHB patients., (© 2024 Wiley‐VCH GmbH.)

Systemic lupus erythematosus (SLE) is a common, potentially fatal autoimmune disease involving a significant inflammatory response. SLE is characterised by failure of self-tolerance and activation of autoreactive lymphocytes, leading to persistent disease. Although current treatments achieve some improvement in patients, some SLE patients are refractory and others relapse after drug withdrawal. The toxicity of current drug regimens, with recurrent infections, together with ongoing inflammation, contribute significantly to the progressive decline in organ function. Therefore, the clinical management of SLE requires more effective and less toxic treatments, ideally inducing complete remission and self-tolerance. In this context, recently developed cell therapies based on mesenchymal stem cells (MSCs) represent a promising and safe strategy in SLE. MSCs inhibit the activation of B cells, prevent the differentiation of CD4⁺ T cells into autoreactive T cells, reprogram macrophages with anti-inflammatory effects and inhibit dendritic cells (DCs), limiting their activity as antigen-presenting cells. In addition, MSCs could induce antigen-specific tolerance by enhancing anergy processes in autoreactive cells - by inhibiting the maturation of antigen-presenting DCs, blocking the T cell receptor (TcR) pathway and secreting inhibitory molecules -, increasing apoptotic activity to eliminate them, and activating regulatory T cells (Tregs) to enhance their proliferation and induction of tolerogenic DCs. Thus, induction of self-tolerance leads to immune balance, keeping inflammation under control and reducing lupus flares., (© 2024 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: Sepsis is a common complication among patients in intensive care units, and has a high mortality rate, with no effective therapies to date. As immunosuppression has become the research focus of sepsis, the regulatory role of dendritic cells (DCs) in the immune response to sepsis has received attention., Objective: To investigate the role of the Wnt/β-catenin signaling pathway in inducing the differentiation of splenic DCs in mice with sepsis caused by cecal ligation and puncture (CLP)., Methods: C57bl/6 mice were randomly divided into three groups, namely the sham, 24 h post-CLP, and 72 h post-CLP groups. Levels of regulatory T cells (Tregs) among splenic mononuclear cells, suppressor T cells (TSs), and surface markers, such as major histocompatibility complex class II (MHC-II), co-stimulatory molecules (CD80 and CD86), negative co-stimulatory molecule death-ligand 1 (PD-L1), CC chemokine receptor-5 (CCR5), and CC chemokine receptor-7 (CCR7), were analyzed via flow cytometry for each group of mice post-surgery. CD11c + DCs were purified from the splenic mononuclear cells of each group, and the expression of β-catenin, Wnt5a, and Wnt3a was detected using RT-PCR and western blotting.Each group of DCs was incubated with LPS-containing culture solution, and the supernatant of the culture solution was collected after 24 hours to detect the level of Tumor necrosis factor-α(TNF-α), interleukin (IL)-6, IL-12, and IL-10., Results: Compared with that in the sham group, the expression of β-catenin, Wnt5a, and Wnt3a in splenic DCs of the other two groups of mice increased with prolonged CLP exposure (P<0.05). Meanwhile, the proportion of Tregs and TSs increased in the mouse spleens after CLP, and levels of DC surface molecules, such as CCR5, CCR7, CD80, CD86, and MHC-II, decreased to different degrees, whereas those of PD-L1 increased. These results suggested that DCs differentiate towards regulatory DCs (regDCs) after CLP in mice. The results of ELISA showed that the longer the exposure time after CLP, the lower the ability of DCs to secrete TNF-α and IL-12, but the higher the level of IL-10 and IL-6., Conclusion: The Wnt/β-catenin signaling pathway activates and induces regDCs differentiation in the splenic DCs of mice with sepsis and participates in the regulation of immune tolerance in the organism., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Upregulation of diverse self-antigens that constitute components of the inflammatory response overlaps spatially and temporally with the emergence of pathogen-derived foreign antigens. Therefore, discrimination between these inflammation-associated self-antigens and pathogen-derived molecules represents a unique challenge for the adaptive immune system. Here, we demonstrate that CD8 + T cell tolerance to T cell-derived inflammation-associated self-antigens is efficiently induced in the thymus and supported by redundancy in cell types expressing these molecules. In addition to thymic epithelial cells, this included thymic eosinophils and innate-like T cells, a population that expressed molecules characteristic for all major activated T cell subsets. We show that direct T cell-to-T cell antigen presentation by minute numbers of innate-like T cells was sufficient to eliminate autoreactive CD8 + thymocytes. Tolerance to such effector molecules was of critical importance, as its breach caused by decreased thymic abundance of a single model inflammation-associated self-antigen resulted in autoimmune elimination of an entire class of effector T cells., (© 2024. The Author(s).)

Pemphigus vulgaris (PV) is a rare autoimmune bullous disease characterized by blistering of the skin and mucosa owing to the presence of autoantibodies against the desmosome proteins desmoglein 3 and occasionally in conjunction with desmoglein 1. Fundamental research into the pathogenesis of PV has revolutionized its treatment and outcome with rituximab, a B-cell-depleting therapy. The critical contribution of B cells to the pathogenesis of pemphigus is well accepted. However, the exact pathomechanism, mechanisms of onset, disease course and relapse remain unclear. In this narrative review, we provide an overview of the fundamental research progress that has unfolded over the past few centuries to give rise to current and emerging therapies. Furthermore, we summarize the multifaceted roles of B cells in PV, including their development, maturation and antibody activity. Finally, we explored how these various aspects of B-cell function contribute to disease pathogenesis and pave the way for innovative therapeutic interventions., Competing Interests: Conflicts of interest A.G. reports fees from AbbVie, Sanofi and UCB (advisory boards, shares, speaker); Eli Lilly, Janssen and Pfizer (advisory boards, shares); Leo Pharma and Regeneron (advisory boards); and GSK (shares). B.H. reports fees from AbbVie and Janssen-Cilag (advisory boards, consultations, educational grants, investigator initiative studies); Novartis Pharma (advisory boards, consultations, investigator initiative studies); Argenx, Boehringer-Ingelheim and UCB Pharma (advisory boards, consultations); Akari Therapeutics and Celgene (consultations, investigator initiative studies); Leo Pharma, Philips, Regeneron, Roche and Sanofi (consultations); and Solenne B.V. (investigator initiative studies); which fees were paid to the institution. A.-L.S., J.B., G.F.H.D., E.A., H.H.P., M.W.-B., G.A.H., P.H., and J.D.L. declare that they have no conflicts of interest regarding the scope of this work., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Autoimmune diseases often arise from conditions where the immune system is compromised. While lymphopenia-induced proliferation (LIP) is crucial for immune system development and maturation, it is also caused by environmental insults, such as infection, and becomes a risk factor for autoimmunity in adults. We used Dsg3H1 TCR transgenic mice, whose T cells are designed to recognize desmogrein-3, a skin antigen, to explore the impact of lymphopenia on post-thymic tolerance. Dsg3H1 mice are known to delete the most highly autoreactive T cells in the thymus, and develop only subtle immune-mediated pathology in the steady state. However, we found that transient lymphopenia induced by total body irradiation (TBI) or cyclophosphamide (CY) results in massive dermatitis in Dsg3H1 mice. The symptoms included expansion and development of self-reactive T cells, their differentiation into CD44high IL-17-producing helper T cells, and severe neutrophilic inflammation. Repopulation of FOXP3+ T regulatory cells after lymphopenia normally occurred, suggesting escape of skin-reactive conventional T cells from control by regulatory T cells. Furthermore, we found that a depletion of the intestinal microbiota by antibiotics prevents CY-induced dermatitis, indicating roles of the commensal intestinal microbiota in LIP and Th17 development in vivo. The current data suggested that post-thymic tolerance of Dsg3H1 mice is established on a fragile balance in the lymphoreplete immune environment and broken by the interplay between lymphopenia and intestinal microbiota. The dynamic phenotypes observed in Dsg3H1 mice prompt a re-evaluation of opportunistic lymphopenia together with the microbiota as pivotal environmental factors, impacting individuals with genetic predispositions for autoimmune diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology.)

T-cell exhaustion is a major contributor to immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T-cell exhaustion, such as programmed death 1, can reinvigorate tumor-specific T cells and activate antitumor immunity in various types of cancer. In this study, we identified that CD106 was specifically expressed in exhausted CD8+ T cells in the TME using single-cell RNA sequencing. High CD106 expression in the TME in clinical samples corresponded to improved response to cancer immunotherapy. CD106 in tumor-specific T cells suppressed antitumor immunity both in vitro and in vivo, and loss of CD106 in CD8+ T cells suppressed tumor growth and improved response to programmed death 1 blockade. Mechanistically, CD106 inhibited T-cell receptor (TCR) signaling by interacting with the TCR/CD3 complex and reducing its surface expression. Together, these findings provide insights into the immunosuppressive role of CD106 expressed in tumor-specific exhausted CD8+ T cells, identifying it as a potential biomarker and therapeutic target for cancer immunotherapy. Significance: CD106 is specifically expressed in tumor-specific exhausted CD8+ T cells and inhibits the TCR signaling pathway by reducing surface expression of the TCR/CD3 complex to suppress antitumor immunity., (©2024 American Association for Cancer Research.)

Introduction: One of the most intriguing aspects of male reproductive physiology is the ability of the epididymis to prevent the mounting of immune responses against the onslaught of foreign antigens carried by spermatozoa while initiating very efficient immune responses versus stressors. Epithelial clear cells are strategically positioned to work in a concerted manner with region-specific heterogeneous subsets of mononuclear phagocytes to survey the epididymal barrier and regulate the balance between inflammation and immune tolerance in the post-testicular environment., Objective: This review aims to describe how clear cells communicate with mononuclear phagocytes to contribute to the unique immune environment in which sperm mature and are stored in the epididymis., Materials/methods: A comprehensive systematic review was performed. PubMed was searched for articles specific to clear cells, mononuclear phagocytes, and epididymis. Articles that did not specifically address the target material were excluded., Results: In this review, we discuss the unexpected roles of clear cells, including the transfer of new proteins to spermatozoa via extracellular vesicles and nanotubes as they transit along the epididymal tubule; and we summarize the immune phenotype, morphology, and antigen capturing, processing, and presenting abilities of mononuclear phagocytes. Moreover, we present the current knowledge of immunoregulatory mechanisms by which clear cells and mononuclear phagocytes may contribute to the immune-privileged environment optimal for sperm maturation and storage., Discussion and Conclusion: Notably, we provide an in-depth characterization of clear cell-mononuclear phagocyte communication networks in the steady-state epididymis and in the presence of injury. This review highlights crucial concepts of mucosal immunology and cellcell interactions, all of which are critical but understudied facets of human male reproductive health., (© 2023 American Society of Andrology and European Academy of Andrology.)

Abstract: Normal pregnancy is a contradictory and complicated physiological process. Although the fetus carries the human leukocyte antigen (HLA) inherited from the paternal line, it does not cause maternal immune rejection. As the only exception to immunological principles, maternal-fetal immune tolerance has been a reproductive immunology focus. In early pregnancy, fetal extravillous trophoblast cells (EVTs) invade decidual tissues and come into direct contact with maternal decidual immune cells (DICs) and decidual stromal cells (DSCs) to establish a sophisticated maternal-fetal crosstalk. This study reviews previous research results and focuses on the establishment and maintenance mechanism of maternal-fetal tolerance based on maternal-fetal crosstalk. Insights into maternal-fetal tolerance will not only improve understanding of normal pregnancy but will also contribute to novel therapeutic strategies for recurrent spontaneous abortion, pre-eclampsia, and premature birth., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

The excessive formation and release of neutrophil extracellular traps (NETs) in sepsis may represent a substantial mechanism contributing to multiorgan damage, which is associated with a poor prognosis. However, the precise role of NETs in mediating the transition from innate immunity to adaptive immunity during the progression of inflammation and sepsis remains incompletely elucidated. In this study, we provide evidence that, despite a reduction in the number of CD4+ T cells in the late stage of sepsis, there is a notable upregulation in the proportion of Tregs. Mechanistically, we have identified that NETs can induce metabolic reprogramming of naive CD4+ T cells through the Akt/mTOR/SREBP2 pathway, resulting in enhanced cholesterol metabolism, thereby promoting their conversion into Tregs and augmenting their functional capacity. Collectively, our findings highlight the potential therapeutic strategy of targeting intracellular cholesterol normalization for the management of immunosuppressed patients with sepsis.

Immunometabolism has been demonstrated to control immune tolerance and the pathogenic events leading to autoimmunity. Compelling experimental evidence also suggests that intracellular metabolic programs influence differentiation, phenotype, proliferation, and effector functions of anti-inflammatory CD4+CD25+Foxp3+ regulatory T (Treg) cells. Indeed, alterations in intracellular metabolism associate with quantitative and qualitative impairments of Treg cells in several pathological conditions. In this review, we summarize the most recent advances linking how metabolic pathways control Treg cell homeostasis and their alterations occurring in autoimmunity. Also, we analyze how metabolic manipulations could be employed to restore Treg cell frequency and function with the aim to create novel therapeutic opportunities to halt immune-mediated disorders., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Peripheral CD8 + T cell tolerance is a checkpoint in both autoimmune disease and anti-cancer immunity. Despite its importance, the relationship between tolerance-induced states and other CD8 + T cell differentiation states remains unclear. Using flow cytometric phenotyping, single-cell RNA sequencing (scRNA-seq), and chromatin accessibility profiling, we demonstrated that in vivo peripheral tolerance to a self-antigen triggered a fundamentally distinct differentiation state separate from exhaustion, memory, and functional effector cells but analogous to cells defectively primed against tumors. Tolerant cells diverged early and progressively from effector cells, adopting a transcriptionally and epigenetically distinct state within 60 h of antigen encounter. Breaching tolerance required the synergistic actions of strong T cell receptor (TCR) signaling and inflammation, which cooperatively induced gene modules that enhanced protein translation. Weak TCR signaling during bystander infection failed to breach tolerance due to the uncoupling of effector gene expression from protein translation. Thus, tolerance engages a distinct differentiation trajectory enforced by protein translation defects., Competing Interests: Declaration of interests I.A.P. receives research funding from AstraZeneca and Bristol-Myers Squibb. H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, Cartography Biosciences, and Orbital Therapeutics, and is an advisor for 10× Genomics, Arsenal Biosciences, Chroma Medicine, and Spring Discovery., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The mechanisms that make and break CD8 + T cell tolerance to self-antigens remain unclear. In this issue of Immunity, Van Der Byl et al. show that tolerant CD8 + T cells rapidly adopt an epigenetically and transcriptionally distinct cell state and exhibit impaired protein translation. Breaking tolerance requires both inflammation and increased antigen exposure to augment MYC expression and restore translation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The intestinal barrier is mainly formed by a monolayer of epithelial cells, which forms a physical barrier to protect the gut tissues from external insults and provides a microenvironment for commensal bacteria to colonize while ensuring immune tolerance. Moreover, various immune cells are known to significantly contribute to intestinal barrier function by either directly interacting with epithelial cells or by producing immune mediators. Fulfilling this function of the gut barrier for mucosal homeostasis requires not only the intrinsic regulation of intestinal epithelial cells (IECs) but also constant communication with immune cells and gut microbes. The reciprocal interactions between IECs and immune cells modulate mucosal barrier integrity. Dysregulation of barrier function could lead to dysbiosis, inflammation, and tumorigenesis. In this overview, we provide an update on the characteristics and functions of IECs, and how they integrate their functions with tissue immune cells and gut microbiota to establish gut homeostasis., (© 2024 The Authors. European Journal of Immunology published by Wiley‐VCH GmbH. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification of CD63 as a specific surface marker, we demonstrate that mature regulatory DCs (mregDCs) migrate to tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 and regulatory T cell differentiation. Transcriptional and metabolic studies showed that mregDC functionality is dependent on the mevalonate biosynthetic pathway and its master transcription factor, SREBP2. We found that melanoma-derived lactate activates SREBP2 in tumor DCs and drives conventional DC transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promoted antitumor CD8 + T cell activation and suppressed melanoma progression. CD63 + mregDCs were found to reside within the lymph nodes of several preclinical tumor models and in the sentinel lymph nodes of patients with melanoma. Collectively, this work suggests that a tumor lactate-stimulated SREBP2-dependent program promotes CD63 + mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME.

Dendritic cells (DCs) are professional antigen-presenting cells and trigger downstream immune responses to antigen while integrating cellular pathogen and damage-associated molecular pattern (PAMP and DAMP) or immunomodulatory signals. In healthy individuals, resting and tolerogenic DCs draining skin and intestine facilitate expansion of regulatory T cells (Treg) to maintain peripheral antigen-specific immune tolerance. In patients with rheumatic diseases, however, DCs activated by PAMPs and DAMPs expand self-reactive effector T cells, including follicular helper T cells that promote the expansion of activated autoreactive B cells, chronic inflammation and end-organ damage. With the development of cellular and nanoparticle (NP)-based self-antigen-specific immunotherapies we here consider the new opportunities and the challenges for restoring immunoregulation in the treatment and prevention of autoimmune inflammatory rheumatic conditions through DCs., Competing Interests: Declaration of competing interest RT reports issued patent 9,017,697 B2: 2006 surrounding technology for targeting DCs for antigen-specific tolerance, and funding from Janssen Biotech Inc. to Uniquest resulting in development and trial of DEN-181., (Copyright © 2024. Published by Elsevier Ltd.)

Coeliac disease is an autoinflammatory condition caused by immune reactions to cereal gluten proteins. Currently, the only available treatment for the condition is a lifelong avoidance of gluten proteins in the diet. There is an unmet need for alternative therapies. Coeliac disease has a strong association with certain HLA-DQ allotypes (DQ2.5, DQ2.2 and DQ8), and these disease-associated HLA-DQ molecules present deamidated gluten peptides to gluten-specific CD4 + T cells. The gluten-specific CD4 + T cells are the drivers of the immune reactions leading to coeliac disease. Once established, the clonotypes of gluten-specific CD4 + T cells persist for decades, explaining why patients must adhere to a gluten-free diet for life. Given the key pathogenic role of gluten-specific CD4 + T cells, tolerance-inducing therapies that target these T cells are attractive for treatment of the disorder. Lessons learned from coeliac disease might provide clues for treatment of other HLA-associated diseases for which the disease-driving antigens are unknown. Thus, intensive efforts have been and are currently implemented to bring an effective tolerance-inducing therapy for coeliac disease. This Review discusses mechanisms of the various approaches taken, summarizing the progress made, and highlights future directions in this field., (© 2024. Springer Nature Limited.)

Sepsis, a multiorgan dysfunction with high incidence and mortality, is caused by an imbalanced host-to-infection immune response. Organ-support therapy improves the early survival rate of sepsis patients. In the long term, those who survive the "cytokine storm" and its secondary damage usually show higher susceptibility to secondary infections and sepsis-induced immunosuppression, in which regulatory T cells (Tregs) are evidenced to play an essential role. However, the potential role and mechanism of Tregs in sepsis-induced immunosuppression remains elusive. In this review, we elucidate the role of different functional subpopulations of Tregs during sepsis and then review the mechanism of sepsis-induced immunosuppression from the aspects of regulatory characteristics, epigenetic modification, and immunometabolism of Tregs. Thoroughly understanding how Tregs impact the immune system during sepsis may shed light on preclinical research and help improve the translational value of sepsis immunotherapy., (© 2024 Wiley‐VCH GmbH.)

Accumulating evidence indicates that aberrant signalling stemming from genetic abnormalities in cancer cells has a fundamental role in their evasion of antitumour immunity. Immune escape mechanisms include enhanced expression of immunosuppressive molecules, such as immune-checkpoint proteins, and the accumulation of immunosuppressive cells, including regulatory T (T reg ) cells, in the tumour microenvironment. Therefore, T reg cells are key targets for cancer immunotherapy. Given that therapies targeting molecules predominantly expressed by T reg cells, such as CD25 or GITR, have thus far had limited antitumour efficacy, elucidating how certain characteristics of cancer, particularly genetic abnormalities, influence T reg cells is necessary to develop novel immunotherapeutic strategies. Hence, T reg cell-targeted strategies based on the particular characteristics of cancer in each patient, such as the combination of immune-checkpoint inhibitors with molecularly targeted agents that disrupt the immunosuppressive networks mediating T reg cell recruitment and/or activation, could become a new paradigm of cancer therapy. In this Review, we discuss new insights on the mechanisms by which cancers generate immunosuppressive networks that attenuate antitumour immunity and how these networks confer resistance to cancer immunotherapy, with a focus on T reg cells. These insights lead us to propose the concept of 'immuno-genomic precision medicine' based on specific characteristics of cancer, especially genetic profiles, that correlate with particular mechanisms of tumour immune escape and might, therefore, inform the optimal choice of immunotherapy for individual patients., (© 2024. Springer Nature Limited.)

The development of therapeutic approaches for the induction of robust, long-lasting and antigen-specific immune tolerance remains an important unmet clinical need for the management of autoimmunity, allergy, organ transplantation and gene therapy. Recent breakthroughs in our understanding of immune tolerance mechanisms have opened new research avenues and therapeutic opportunities in this area. Here, we review mechanisms of immune tolerance and novel methods for its therapeutic induction., (© 2023. Springer Nature Limited.)

Thymic negative selection of the T cell receptor (TCR) repertoire is essential for establishing self-tolerance and acquired allograft tolerance following organ transplantation. However, it is unclear whether and how peripheral clonal deletion of alloreactive T cells induces transplantation tolerance. Here, we establish that programmed cell death protein 1 (PD-1) is a hallmark of alloreactive T cells and is associated with clonal expansion after alloantigen encounter. Moreover, we found that diphtheria toxin receptor (DTR)-mediated ablation of PD-1 + cells reshaped the TCR repertoire through peripheral clonal deletion of alloreactive T cells and promoted tolerance in mouse transplantation models. In addition, by using PD-1-specific depleting antibodies, we found that antibody-mediated depletion of PD-1 + cells prevented heart transplant rejection and the development of experimental autoimmune encephalomyelitis (EAE) in humanized PD-1 mice. Thus, these data suggest that PD-1 is an attractive target for peripheral clonal deletion and induction of immune tolerance.

Dendritic cells (DCs), the most efficient antigen-presenting cells (APCs), bridge the innate and adaptive immune systems. As such, the turn-over of DCs is critical during autoimmune responses, and the dysregulation of DC apoptosis could cause severe immune destruction in the host. For example, reduction of immunogenic DCs by increased apoptosis could lead to immune tolerance to pathogen infection that might allow exposure of nuclear autoantigens, whereas reduced apoptosis could result in long-term lymphocyte activation to break the immune tolerance for the development of autoimmune disease. Thus, keeping a balance between survival and apoptosis of DCs is crucial to maintain immune homeostasis. In this review, we summarize the recent development on the factors inducing DC apoptosis and their underlying mechanisms to provide insights into the immunopathogenesis of some autoimmune diseases, which could lead to effective therapeutic interventions in the clinics., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response 1-4 . The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1) 5 . Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms 5 , indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals 6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism., (© 2024. The Author(s).)

The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens 1,2 . Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (T reg ) cell development and function have been identified 3,4 , less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive T reg cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing 5-7 and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector T reg (eT reg ) cell function. eT reg cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103 + SIRPα + dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206 + macrophages and eT reg cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies., (© 2024. The Author(s).)

Background: Preeclampsia is a pregnancy-specific disorder that always causes maternal and fetal serious adverse outcome. Disturbances in maternal immune tolerance to embryo at the maternal-fetal interface (MFI) may be associated with preeclampsia onset. Recent studies have revealed the reduced expression pattern of HLA-F at the MFI in preeclampsia, while the mechanism of it mediating maternal fetal immune tolerance has not been revealed., Methods: Single-cell RNA sequencing on placental decidua was performed to reveal the immune disturbances landscape at the MFI in preeclampsia. Human Jar cells and NK-92MI cells were employed to study the role of HLA-F in trophoblasts and lymphocyte., Results: A total of 101,250 cells were classified into 22 cell clusters. Disease-related IGFBP1+SPP1+ extracellular villus trophoblast (EVT) was identified in the preeclamptic placental decidua, accompanied by newly discovered immune cellular dysfunction such as reduced ribosomal functions of NK populations and abnormal expression of antigen-presenting molecules in most cell clusters. Certain genes that are characteristic of the intermediate stage of myeloid or EVT cell differentiation were found to have unexplored but important functions in the pathogenesis of preeclampsia; specifically, we detected enhanced cell cross-talk between IGFBP1+SPP1+ EVT2 or SPP1+M1 cells and their receptor cell populations at the MFI of PE patients compared to controls. With respect to HLA-F, mIF staining confirmed its reduced expression in PE samples compared to controls. Over-expression of HLA-F in Jar cells promoted cell proliferation, invasion, and migration while under-expression had the opposite effect. In NK-92MI cells, over-expression of HLA-F increased the secretion of immunoregulation cytokines such as CSF1 and CCL22, and promoted adaptive NKG2C+NK cell transformation., Conclusions: We revealed the immune disturbance landscape at the MFI in preeclampsia. Our findings regarding cellular heterogeneity and immune cellular dysfunction, as revealed by scRNA-seq, and the function of HLA-F in cells provide new perspectives for further investigation of their roles in the pathogenesis of preeclampsia, and then provide potential new therapeutic target., Competing Interests: Author SD was employed by company Inovarion. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luo, Liu, Guo, Xu, Li, Yi, Fournier, Degrelle, Zitouni, Hernandez, Liu, Huang and Yue.)

Purpose: Ongoing angiogenesis renders the tumor endothelium unresponsive to inflammatory cytokines and interferes with adhesion of leukocytes, resulting in escape from immunity. This process is referred to as tumor endothelial cell anergy. We aimed to investigate whether anti-angiogenic agents can overcome endothelial cell anergy and provide pro-inflammatory conditions., Experimental Design: Tissues of renal cell carcinoma (RCC) patients treated with VEGF pathway-targeted drugs and control tissues were subject to RNAseq and immunohistochemical profiling of the leukocyte infiltrate. Analysis of adhesion molecule regulation in cultured endothelial cells, in a preclinical model and in human tissues was performed and correlated to leukocyte infiltration., Results: It is shown that treatment of RCC patients with the drugs sunitinib or bevacizumab overcomes tumor endothelial cell anergy. This treatment resulted in an augmented inflammatory state of the tumor, characterized by enhanced infiltration of all major leukocyte subsets, including T cells, regulatory T cells, macrophages of both M1- and M2-like phenotypes and activated dendritic cells. In vitro, exposure of angiogenic endothelial cells to anti-angiogenic drugs normalized ICAM-1 expression. In addition, a panel of tyrosine kinase inhibitors was shown to increase transendothelial migration of both non-adherent and monocytic leukocytes. In primary tumors of RCC patients, ICAM-1 expression was found to be significantly increased in both the sunitinib and bevacizumab-treated groups. Genomic analysis confirmed the correlation between increased immune cell infiltration and ICAM-1 expression upon VEGF-targeted treatment., Conclusion: The results support the emerging concept that anti-angiogenic therapy can boost immunity and show how immunotherapy approaches can benefit from combination with anti-angiogenic compounds., (© 2022. The Author(s).)

Cell atlases of human tolerogenic milieus guide transformative immunotherapies.

The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours 1-4 . The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8 + T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14 high myeloid cells in hepatic zone 2. CD14 + CD8 + T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14 + CD8 + T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14 + CD8 + T cell profile can be recapitulated by the acquisition of membrane proteins-including the lipopolysaccharide receptor complex-from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14 + CD8 + T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14 + CD8 + T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut-liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8 + T cells with immunomodulatory ability., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

One of the main issues of the peculiarities of the immune reactions of the gastrointestinal tract is the mechanisms of ensuring tolerance to food antigens. Concentrations of antibodies to food antigens actually reflect the state of the intestinal mucosa barrier function, and the degree of penetration of antigens into the blood determines the level of immune response to them. The aim of the study was to determine the risk criteria for violation of tolerance to food antigens. Material and methods . The study included the results of a survey and examination of 1334 adults living in the north of the European part of the Russian Federation, including 1100 born in the North, of which 970 were women and 364 were men. The average age of the respondents was 45.5±1.0 years. The comparison group consisted of 344 patients with pathology of the gastrointestinal tract who applied to the medical company "Biocor". The content of immunoglobulins (Ig) G to food antigens, total IgA, cytokines (tumor necrosis factor α, interleukin-6, interleukin-4) in blood serum were determined by enzyme immunoassay. Results . Rural residents often (more than 28%) have elevated concentrations of IgG to potato, river fish, wheat and rye antigens. Urban residents have the most pronounced decrease in tolerance to food antigens of chicken, cod, beef and pork. In healthy individuals, elevated (>100 ME/ml) concentrations of antibodies to meat products are recorded in the range of 11.3-13.9%, to dairy antigens - 11.5-14.1%, cereals - 11.9-13.4%. Slightly less frequently, elevated concentrations of antibodies to fish antigens (7.5-10.1%), vegetables (3.8-7.0%) and fruits (4.9-6.5%) are detected. In inflammatory and oncological diseases of the gastrointestinal tract, the content of antibodies to food antigens increases sharply. On average, the frequency of impaired tolerance to food antigens in patients is 2.7-6.1 times higher than in healthy individuals. Conclusion . Violation of tolerance to food antigens is associated with an increase in blood pro-inflammatory cytokines, mainly interleukin-6. In practically healthy individuals, a decrease in tolerance to food antigens is associated with a deficiency of blood IgA. The risk criteria for violation of the diet or consumption of low-quality foods may be an increase in the frequency of detection of elevated concentrations of antibodies to meat products in 14.6±3.0%, fish - 10.7±2.3%, cereals - 13.7±1.6%, dairy products - 14.8±1.5%, vegetables - 7.8±2.4% and fruits - 6.9±5.8%., Competing Interests: The authors declare no conflicts of interest., (Copyright© GEOTAR-Media Publishing Group.)

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are key enzymes for tryptophan degradation, regulating immune tolerance during pregnancy. The intrauterine renin-angiotensin system is also involved in the progression of a healthy pregnancy. Angiotensin(1-7) maintains the integrity of fetal membranes via counteracting the pro-inflammatory actions of Angiotensin II. No data are available on placental Angiotensin(1-7) co-expression with TDO. We aimed to characterize TDO mRNA expression and its localization in different areas of the placenta of physiological pregnancies delivered at term; its co-expression with Angiotensin(1-7) and its correlation with the plasma kynurenine/tryptophan (Kyn/Trp) ratio was investigated. This prospective observational study included a nonconsecutive series of 20 singleton uncomplicated pregnancies delivered vaginally. TDO mRNA was expressed in both maternal and fetal sides of the placentas and TDO protein also in the villi and it was co-expressed with IDO1 in almost half of the placental cells at these sites. The percentage of TDO + and IDO1 + cells appeared to be influenced by maternal pre-gestational smoking and newborn weight. A strong correlation was found between the percentage of TDO + and IDO1 + cells in the villi. TDO + cells also expressed Angiotensin(1-7), with a higher percentage on the fetal side and in the villi compared to the maternal one. Kyn/Trp plasma ratio was not correlated with IDO and TDO expression nor with the patient's characteristics. Collectively, our data indicate that TDO is detectable in placental tissue and is co-expressed with IDO and with Angiotensin(1-7) + on the fetal side and in the villi., Competing Interests: Decleration of Competing Interest The authors report no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Understanding maternal immune tolerance is crucial for the development of therapeutics for immunological pregnancy complications. Decidual regulatory T cells (Tregs) play a pivotal role in the maintenance of maternal immune tolerance. Using a murine allogeneic pregnancy model in the current study, we identified the up-regulation of gonadotropin-releasing hormone receptor (GnRHR) in decidual T cell subsets including CD4 + conventional T cells, CD8 + T cells, and CD4 + Foxp3 + Tregs. Using a lentivirus-mediated GnRHR overexpression system and a GnRHR agonist, we found that GnRHR activation decreased the expression of Treg functional molecules such as IL10 (IL-10), IL-35 subunit EBI3 (Ebi3), IL2RA (CD25), TNFRSF18 (GITR), ICOS , and Treg master regulator FOXP3 . The functional analysis indicated that GnRHR activation impairs the ability of Tregs to inhibit conventional T cell proliferation. We also revealed that GnRHR activation suppressed the mechanistic target of rapamycin (mTOR) signaling in GnRHR-overexpressing splenic Tregs (Wild type C57BL/6 J background) and decidual Tregs. MHY1485, a potent mTOR activator, effectively abolished the effect of the GnRHR agonist and promoted the immunosuppressive capability of Tregs. Furthermore, in an adoptive transfer model, Treg-specific GnRHR knockdown increased Foxp3 expression in decidual Tregs while decreasing the production of IFN-γ and IL-17 in decidual effector CD4 + T cells and reducing the production of IFN-γ in decidual effector CD8 + T cells. Taken together, the present study unveils a novel mechanism by which the immunosuppressive function of decidual Tregs is modulated, and deepens our understanding of maternal immune tolerance.

Gastrointestinal health depends on the adaptive immune system tolerating the foreign proteins in food 1,2 . This tolerance is paradoxical because the immune system normally attacks foreign substances by generating inflammation. Here we addressed this conundrum by using a sensitive cell enrichment method to show that polyclonal CD4 + T cells responded to food peptides, including a natural one from gliadin, by proliferating weakly in secondary lymphoid organs of the gut-liver axis owing to the action of regulatory T cells. A few food-specific T cells then differentiated into T follicular helper cells that promoted a weak antibody response. Most cells in the expanded population, however, lacked canonical T helper lineage markers and fell into five subsets dominated by naive-like or T follicular helper-like anergic cells with limited capacity to form inflammatory T helper 1 cells. Eventually, many of the T helper lineage-negative cells became regulatory T cells themselves through an interleukin-2-dependent mechanism. Our results indicate that exposure to food antigens causes cognate CD4 + naive T cells to form a complex set of noncanonical hyporesponsive T helper cell subsets that lack the inflammatory functions needed to cause gut pathology and yet have the potential to produce regulatory T cells that may suppress it., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Glycans are carbohydrates that are made by all organisms and covalently conjugated to other biomolecules. Glycans cover the surface of both human cells and pathogens and are fundamental to defining the identity of a cell or an organism, thereby contributing to discriminating self from nonself. As such, glycans are a class of 'Self-Associated Molecular Patterns' that can fine-tune host inflammatory processes. In fact, glycans can be sensed and recognized by a variety of glycan-binding proteins (GBP) expressed by immune cells, such as galectins, siglecs, and C-type lectins, which recognize changes in the cellular glycosylation, instructing both pro-inflammatory and anti-inflammatory responses. In this review, we introduce glycans as cell-identification structures, discussing how glycans modulate host-pathogen interactions and how they can fine-tune inflammatory processes associated with infection, inflammation and autoimmunity. Finally, from the clinical standpoint, we discuss how glycoscience research can benefit life sciences and clinical medicine by providing a source of valuable biomarkers and therapeutic targets for immunity., (© 2022 Federation of European Biochemical Societies.)