Non-self Antigens Research Articles

A clinical effect of disease-modifying treatment on alloimmunisation in transfused patients with myelodysplastic syndromes: data from a population-based study.

Alloimmunisation against blood products is an adverse event, causing time-consuming compatibility testing. Current literature has not yet identified the influence of treatment on the risk of alloimmunisation in patients with myelodysplastic syndromes (MDS). An observational, population-based study, using the HemoBase registry, was performed including all transfused patients who were diagnosed with MDS between 2005 and 2017 in Friesland, a province in the Netherlands. Information about transfusion dates, types, and treatment regimens was collected from the health records. Blood products were matched for ABO and Rhesus D. The effect of disease-modifying treatment was estimated with incidence rates and a Cox time-dependent analysis. 233 patients were included in this study, with a median follow-up of 13.0 months. Alloimmunisation occurred in 21 patients (9.0%) and predominantly occurred early in follow-up. Three (5%) and 18 (11%) alloimmunisation events occurred in patients with and without disease-modifying treatment, respectively. The hazard ratio for alloimmunisation without treatment compared to during treatment was 2.7 (95% CI: 0.35-20.0), with incidence rates of 7.18 and 2.41 per 100 patient-years, respectively. In a non-selected real-world population of MDS patients receiving blood transfusions, the percentage of patients with alloimmunisation was below 10%. The results of this study support the hypothesis that disease-modifying treatment affects the ability of the immune system to mount an antibody response to non-self blood group antigens.

Tissues and Organs of the Immune System of Dromedary Camel (Camelus dromedarius): A Comparative Review

The immune system is formed of sets of tissues and organs that have the ability to discern self-substances from non-self (antigen) substances and to destroy or inactivate the latter. This review presents a literary survey of what has been written on the subject of the histology of the immune system in dromedary camels and compared the structure of these tissue and organs to that of ruminants.

Epitope-Specific T Cell Receptor Data and Tools in the Immune Epitope Database.

T cells play a critical role in the response of the immune system to non-self antigens. The Immune Epitope Database (IEDB) continuously curates published T cell data, among other immune-related data, and allows users to create custom queries based on their research interests and aims. The IEDB's companion site, the IEDB Analysis Resource, features a number of tools for analysis and prediction of immune epitopes; these include TCRMatch, a new tool used to predict candidate epitopes for T cell receptors with unknown specificity. Together these resources enable users to browse and filter large amounts of published data as well as generate hypotheses to guide future experiments.

Immunotherapy Approaches in HPV-Associated Head and Neck Cancer

Simple SummaryHuman papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) represents a distinct entity with molecular, pathological, and clinical features that lead to an improved response to standard therapy and a favorable prognosis compared to HPV-negative HNSCC. In this review we expound on the developing role of immunotherapy in HPV-positive HNSCC and highlight the clinical rationale and ongoing trials investigating novel therapeutic approaches.Immunotherapy approaches for head and neck squamous cell carcinoma (HNSCC) are rapidly advancing. Human papillomavirus (HPV) has been identified as a causative agent in a subset of oropharyngeal cancers (OPC). HPV-positive OPC comprises a distinct clinical and pathologic disease entity and has a unique immunophenotype. Immunotherapy with anti-PD1 checkpoint inhibitors has exhibited improved outcomes for patients with advanced HNSCC, irrespective of HPV status. To date, the clinical management of HPV-positive HNSCC and HPV-negative HNSCC has been identical, despite differences in the tumor antigens, immune microenvironment, and immune signatures of these two biologically distinct tumor types. Numerous clinical trials are underway to further refine the application of immunotherapy and develop new immunotherapy approaches. The aim of this review is to highlight the developing role of immunotherapy in HPV-positive HNSCC along with the clinical evidence and preclinical scientific rationale behind emerging therapeutic approaches, with emphasis on promising HPV-specific immune activators that exploit the universal presence of foreign, non-self tumor antigens.

Computational cancer neoantigen prediction: current status and recent advances.

Over the last few decades, immunotherapy has shown significant therapeutic efficacy in a broad range of cancer types. Antitumor immune responses are contingent on the recognition of tumor-specific antigens, which are termed neoantigens. Tumor neoantigens are ideal targets for immunotherapy since they can be recognized as non-self antigens by the host immune system and thus are able to elicit an antitumor T-cell response. There are an increasing number of studies that highlight the importance of tumor neoantigens in immunoediting and in the sensitivity to immune checkpoint blockade. Therefore, one of the most fundamental tasks in the field of immuno-oncology research is the identification of patient-specific neoantigens. To this end, a plethora of computational approaches have been developed in order to predict tumor-specific aberrant peptides and quantify their likelihood of binding to patients' human leukocyte antigen molecules in order to be recognized by T cells. In this review, we systematically summarize and present the most recent advances in computational neoantigen prediction, and discuss the challenges and novel methods that are being developed to resolve them.

Prospective Tracking of Donor-Reactive T-Cell Clones in the Circulation and Rejecting Human Kidney Allografts.

BackgroundAntigen recognition of allo-peptides and HLA molecules leads to the activation of donor-reactive T-cells following transplantation, potentially causing T-cell-mediated rejection (TCMR). Sequencing of the T-cell receptor (TCR) repertoire can be used to track the donor-reactive repertoire in blood and tissue of patients after kidney transplantation.Methods/DesignIn this prospective cohort study, 117 non-sensitized kidney transplant recipients with anti-CD25 induction were included. Peripheral mononuclear cells (PBMCs) were sampled pre-transplant and at the time of protocol or indication biopsies together with graft tissue. Next-generation sequencing (NGS) of the CDR3 region of the TCRbeta chain was performed after donor stimulation in mixed lymphocyte reactions to define the donor-reactive TCR repertoire. Blood and tissue of six patients experiencing a TCMR and six patients without rejection on protocol biopsies were interrogated for these TCRs. To elucidate common features of T-cell clonotypes, a network analysis of the TCR repertoires was performed.ResultsAfter transplantation, the frequency of circulating donor-reactive CD4 T-cells increased significantly from 0.86 ± 0.40% to 2.06 ± 0.40% of all CD4 cells (p < 0.001, mean dif.: -1.197, CI: -1.802, -0.593). The number of circulating donor-reactive CD4 clonotypes increased from 0.72 ± 0.33% to 1.89 ± 0.33% (p < 0.001, mean dif.: -1.168, CI: -1.724, -0.612). No difference in the percentage of donor-reactive T-cells in the circulation at transplant biopsy was found between subjects experiencing a TCMR and the control group [p = 0.64 (CD4+), p = 0.52 (CD8+)]. Graft-infiltrating T-cells showed an up to six-fold increase of donor-reactive T-cell clonotypes compared to the blood at the same time (3.7 vs. 0.6% and 2.4 vs. 1.5%), but the infiltrating TCR repertoire was not reflected by the composition of the circulating TCR repertoire despite some overlap. Network analysis showed a distinct segregation of the donor-reactive repertoire with higher modularity than the overall TCR repertoire in the blood. These findings indicate an unchoreographed process of diverse T-cell clones directed against numerous non-self antigens found in the allograft.ConclusionDonor-reactive T-cells are enriched in the kidney allograft during a TCMR episode, and dominant tissue clones are also found in the blood.Trial RegistrationClinicaltrials.gov: NCT: 03422224 (https://clinicaltrials.gov/ct2/show/NCT03422224).

Type 1 Cytotoxic T Cells Increase in Placenta after Intrauterine Inflammation.

CD8+ T cells recognize non-self antigen by MHC class I molecules and kill the target cells by the release of proinflammatory cytokines such as interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). Our group previously reported an increase of CD8+ T‐cell trafficking in the placenta with exposure to Lipopolysaccharides (LPS). CD8+ cytotoxic T cells have been classified into distinct subsets based upon cytokine production: Tc1 cells produce IFN-γ, Tc2 cells produce interleukin 4 (IL-4). Accordingly, the purpose of this research is to analyze the subsets of placenta CD8+ T cells. We hypothesized that LPS injection would induce a change of properties of CD8+ T cell and Tc1/Tc2 ratio. We investigated the subsets of CD8+ T cell infiltration to placenta and their specific function in response to LPS-induced inflammation in a mouse model. At embryonic (E) day 17, pregnant CD-1 dams received an intrauterine injection of 25 µg LPS in100 μl PBS or 100 μl of PBS only. Flow cytometry was used to quantify CD8+ T cells, evaluate the phenotype and subtypes, and detect markers of Tc1 and Tc2 cells in placenta, at 6 hours and 24 hours post injection (hpi). Intracellular staining and flow cytometry were performed to characterize cytokines produced by CD8+ T cells. Standard statistical analysis were employed. After 6 and 24 hours of LPS injection, total CD8 T cells increased (P<0.05). Tc1 cells expanded (P<0.05) in LPS-treated dams compared with the PBS group. The Tc1/Tc2 ratio was significantly higher in the LPS group than the PBS group (P<0.05). The expression of TNF-α and IFN-γ were increased in LPS group both at 6hpi and 24 hpi (P<0.05). We identified functional placental CD8+ T cell subtypes and found a significant increase ratio of Tc1/Tc2. Following IUI, CD8+ T cells induced inflammatory response in the placenta primarily via the production of Type 1 cytokines such as IFN-γ and TNF-α. We have provided evidence of a Tc1-bias response and cytokines in the mouse model of IUI.

Placental Immune Tolerance and Organ Transplantation: Underlying Interconnections and Clinical Implications.

The immune system recognizes and attacks non-self antigens, making up the cornerstone of immunity activity against infection. However, during organ transplantation, the immune system also attacks transplanted organs and leads to immune rejection and transplantation failure. Interestingly, although the embryo and placenta are semi-allografts, like transplanted organs, they can induce maternal tolerance and be free of a vigorous immune response. Also, embryo or placenta-related antibodies might adversely affect subsequent organ transplantation despite the immune tolerance during pregnancy. Therefore, the balance between the immune tolerance in maternal-fetal interface and normal infection defense provides a possible desensitization and tolerance strategy to improve transplantation outcomes. A few studies on mechanisms and clinical applications have been performed to explore the relationship between maternal-fetal immune tolerance and organ transplantation. However, up to now, the mechanisms underlying maternal-fetal immune tolerance remain vague. In this review, we provide an overview on the current understanding of immune tolerance mechanisms underlying the maternal-fetal interface, summarize the interconnection between immune tolerance and organ transplantation, and describe the adverse effect of pregnancy alloimmunization on organ transplantation.

Neoantigens in MDS Are Associated with Two Novel CD4+ T Cell Subsets and Improved Overall Survival

BackgroundThe immune system has been shown to be important in the pathophysiology of MDS. Adaptive immunity relies on T cells ability to discriminate between self and non-self antigens in the context of a surface bound MHC protein structure. Genomic changes occurring in acquired somatic mutations can encode novel amino acid sequences, which if translated and presented by the MHC are termed a neoantigen.To establish the impact of neoantigens in MDS we have combined a predictive algorithm to screen cases for the presence of neoantigens together with mass cytometry by time of flight (CyTOF) to identify neoantigen-related immune signatures.ResultsMutation screening was performed on 204 MDS patients using our established gene panel targeting mutations commonly occurring in MDS (Mohemdali, Leukaemia 2015). Neoantigen-MHC affinity was predicted using NetMHCpan3.0 with neoantigen affinities ranked against 400,000 naturally occurring peptides. Those in the top 2% of peptides were classed as predicted neoantigens.In a multi-variate analysis of overall survival, higher numbers of mutations were associated with a poorer outcome (HR 2.71 95%CI 1.28-5.73, p <0.01). In a subset of 72 low risk MDS cases (by IPSS) the presence of neoantigen was protective (HR 0.21 95% CI 0.05-0.84, p <0.05) (fig 1). There was no survival benefit in the presence of neoantigens in high risk MDS.To look for an immune signature in MDS, we performed deep immunophenotyping on 44 MDS cases and 8 age-matched healthy donors (HDs). Peripheral blood mononuclear cells (PBMCs) were stained with 35 metal-tagged antibodies and analysed using CyTOF. Automated clustering methods (t-distributed stochastic neighbour embedding (t-SNE), spanning-tree progression analysis of density-normalized events (SPADE) and in-house clustering) were used to identify T cell subsets. As expected, T regulatory cells were increased in MDS cases when compared to HDs (7.2% vs 4.9% p <0.00001). However, within MDS there was an increase in the recently described Treg B (Kordasti, Blood 2016) in RAEB (4.9% vs 3.6%, p <0.05). These Tregs have been shown to be activated, more suppressive, quicker in responding to IL-2 by phosphorylating STAT5 and Treg specific demethylated region (TSDR) is unmethylated. Of note, there was no difference in abundance of Tregs or other T cell subsets based on presence or absence of mutation or neoantigen.To assess other features of immune suppression we analysed expression of immune checkpoints. While there was no difference in percentage of PD1 positive cells as a proportion of T cells between MDS and HD, neoantigen positive patients had higher PD1+ T cells compared to negative cases (0.77 vs 1.69% p <0.005). To explore the phenotype of PD1 positive PBMCs further we used unsupervised clustering and identified 23 phenotypically distinct clusters of PD1 high cells (fig 2). Neoantigen positive cases had significantly lower numbers of two distinct PD1hi CD4+ T cell subsets (p<0.05). Using Marker Enrichment Modelling (MEM) to better characterise these clusters, we have shown one cluster to be part of the Treg B subpopulation and the other within T effectors (fig 3) (Diggins, Nature Methods 2017). No significant differences in numbers of these cells was seen between other subtypes of MDS, including presence or absence of mutations, or between MDS and HD.DiscussionUsing multi-dimensional analysis we have shown that increased blast counts are associated with an increase in more suppressive and proliferating Tregs (Treg B). The findings of increased numbers of PD1hi T-cells and also two specific CD4+ subsets implies a more immunosenescent phenotype in neoantigen negative MDS. The lack of this association when comparing mutation positive and negative cases suggests that this immune signature is dependent on the patient-specific interaction of the mutation with HLA type rather than driven by the presence of a mutation per se.This work demonstrates clearly for the first time the protective role of neoantigens in low risk MDS. By combining knowledge of host immune factors and tumour characteristics we have identified two novel subsets of PD1 upregulated CD4+ T cells that may play an important role in tumour surveillance and identifies cells likely to be susceptible to PD1 blockade. Further work to understand the mechanistic effects of PD1 blockade on these subsets will be crucial to identifying patients most likely to respond to checkpoint inhibition. [Display omitted] DisclosuresKulasekararaj:Akari Therapeutics Plc: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria; Ra Pharmaceuticals: Consultancy, Honoraria; Achillion pharmaceuticals: Consultancy, Honoraria. Irish:Cytobank Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Incyte: Research Funding. Kordasti:Celgene: Research Funding.

Highly Sensitized Patients Are Well Served by Receiving a Compatible Organ Offer Based on Acceptable Mismatches.

Highly sensitized kidney patients accrue on the transplant waiting list due to their broad immunization against non-self Human Leucocyte Antigens (HLA). Although challenging, the best option for highly sensitized patients is transplantation with a crossmatch negative donor without any additional therapeutic intervention. The Eurotransplant Acceptable Mismatch (AM) program was initiated more than 30 years ago with the intention to increase the chance for highly sensitized patients to be transplanted with such a compatible donor. The AM program allows for enhanced transplantation to this difficult to transplant patient group by allocating deceased donor kidneys on the basis of a match with the recipient’s own HLA antigens in combination with predefined acceptable antigens. Acceptable antigens are those HLA antigens towards which the patients has never formed antibodies, as determined by extensive laboratory testing. By using this extended HLA phenotype for allocation and giving priority whenever a compatible donor organ becomes available, organ offers are made for roughly 80% of patients in this program. Up till now, more than 1700 highly sensitized patients have been transplanted through the AM program. Recent studies have shown that the concept of acceptable mismatches being truly immunologically acceptable holds true for both rejection rates and long-term graft survival. Patients that were transplanted through the AM program had a similar rejection incidence and long-term graft survival rates identical to non-sensitized patients transplanted through regular allocation. However, a subset of patients included in the AM program does not receive an organ offer within a reasonable time frame. As these are often patients with a rare HLA phenotype in comparison to the Eurotransplant donor population, extension of the donor pool for these specific patients through further European collaboration would significantly increase their chances of being transplanted. For those patients that will not benefit from such strategy, desensitization is the ultimate solution.

Potential Mimicry of Viral and Pancreatic β Cell Antigens Through Non-Spliced and cis-Spliced Zwitter Epitope Candidates in Type 1 Diabetes.

Increasing evidence suggests that post-translational peptide splicing can play a role in the immune response under pathological conditions. This seems to be particularly relevant in Type 1 Diabetes (T1D) since post-translationally spliced epitopes derived from T1D-associated antigens have been identified among those peptides bound to Human Leucocyte Antigen (HLA) class I and II complexes. Their immunogenicity has been confirmed through CD4+ and CD8+ T cell-mediated responses in T1D patients. Spliced peptides theoretically have a large sequence variability. This might increase the frequency of viral-human zwitter peptides, i.e. peptides that share a complete sequence homology irrespective of whether they originate from human or viral antigens, thereby impinging upon the discrimination between self and non-self antigens by T cells. This might increase the risk of autoimmune responses triggered by viral infections. Since enteroviruses and other viral infections have historically been associated with T1D, we investigated whether cis-spliced peptides derived from selected viruses might be able to trigger CD8+ T cell-mediated autoimmunity. We computed in silico viral-human non-spliced and cis-spliced zwitter epitope candidates, and prioritized peptide candidates based on: (i) their binding affinity to HLA class I complexes, (ii) human pancreatic β cell and medullary thymic epithelial cell (mTEC) antigens’ mRNA expression, (iii) antigen association with T1D, and (iv) potential hotspot regions in those antigens. Neglecting potential T cell receptor (TCR) degeneracy, no viral-human zwitter non-spliced peptide was found to be an optimal candidate to trigger a virus-induced CD8+ T cell response against human pancreatic β cells. Conversely, we identified some zwitter peptide candidates, which may be produced by proteasome-catalyzed peptide splicing, and might increase the likelihood of pancreatic β cells recognition by virus-specific CD8+ T cell clones, therefore promoting β cell destruction in the context of viral infections.

An Integrated Genomic, Proteomic, and Immunopeptidomic Approach to Discover Treatment-Induced Neoantigens.

All nucleated mammalian cells express major histocompatibility complex (MHC) proteins that present peptides on cell surfaces for immune surveillance. These MHC-presented peptides (pMHC) are necessary for directing T-cell responses against cells harboring non-self antigens derived from pathogens or from somatic mutations. Alterations in tumor-specific antigen repertoires — particularly novel MHC presentation of mutation-bearing peptides (neoantigens) — can be potent targets of anti-tumor immune responses. Here we employed an integrated genomic and proteomic antigen discovery strategy aimed at measuring how interferon gamma (IFN-γ) alters antigen presentation, using a human lymphoma cell line, GRANTA-519. IFN-γ treatment resulted in 126 differentially expressed proteins (2% of all quantified proteins), which included components of antigen presentation machinery and interferon signaling pathways, and MHC molecules themselves. In addition, several proteasome subunits were found to be modulated, consistent with previous reports of immunoproteasome induction by IFN-γ exposure. This finding suggests that a modest proteomic response to IFN-γ could create larger alteration to cells’ antigen/epitope repertoires. Accordingly, MHC immunoprecipitation followed by mass spectrometric analysis of eluted peptide repertoires revealed exclusive signatures of IFN-γ induction, with 951 unique peptides reproducibly presented by MHC-I and 582 presented by MHC-II. Furthermore, an additional set of pMHCs including several candidate neoantigens, distinguished control and the IFN-γ samples by their altered relative abundances. Accordingly, we developed a classification system to distinguish peptides which are differentially presented due to altered expression from novel peptides resulting from changes in antigen processing. Taken together, these data demonstrate that IFN-γ can re-shape antigen repertoires by identity and by abundance. Extending this approach to models with greater clinical relevance could help develop strategies by which immunopeptide repertoires are intentionally reshaped to improve endogenous or vaccine-induced anti-tumor immune responses and potentially anti-viral immune responses.

Genomic Intelligence as Über Bio-Cybersecurity: The Gödel Sentence in Immuno-Cognitive Systems

This paper gives formal foundations and evidence from gene science in the post Barbara McClintock era that the Gödel Sentence, far from being an esoteric construction in mathematical logic, is ubiquitous in genomic intelligence that evolved with multi-cellular life. Conditions uniquely found in the Adaptive Immune System (AIS) and Mirror Neuron System (MNS), termed the genomic immuno-cognitive system, coincide with three building blocks in computation theory of Gödel, Turing and Post (G-T-P). (i) Biotic elements have unique digital identifiers with gene codes executing 3D self-assembly for morphology and regulation of the organism using the recursive operation of Self-Ref (Self-Reference) with the other being a self-referential projection of self. (ii) A parallel offline simulation meta/mirror environment in 1–1 relation to online machine executions of self-codes gives G-T-P Self-Rep (Self-Representation). (iii) This permits a digital biotic entity to self-report that it is under attack by a biotic malware or non-self antigen in the format of the Gödel sentence, resulting in the “smarts” for contextual novelty production. The proposed unitary G-T-P recursive machinery in AIS and in MNS for social cognition yields a new explanation that the Interferon Gamma factor, known for friend-foe identification in AIS, is also integral to social behaviors. New G-T-P bio-informatics of AIS and novel anti-body production is given with interesting testable implications for COVID-19 pathology.

TCRMatch: Predicting T-Cell Receptor Specificity Based on Sequence Similarity to Previously Characterized Receptors.

The adaptive immune system in vertebrates has evolved to recognize non-self antigens, such as proteins expressed by infectious agents and mutated cancer cells. T cells play an important role in antigen recognition by expressing a diverse repertoire of antigen-specific receptors, which bind epitopes to mount targeted immune responses. Recent advances in high-throughput sequencing have enabled the routine generation of T-cell receptor (TCR) repertoire data. Identifying the specific epitopes targeted by different TCRs in these data would be valuable. To accomplish that, we took advantage of the ever-increasing number of TCRs with known epitope specificity curated in the Immune Epitope Database (IEDB) since 2004. We compared seven metrics of sequence similarity to determine their power to predict if two TCRs have the same epitope specificity. We found that a comprehensive k-mer matching approach produced the best results, which we have implemented into TCRMatch, an openly accessible tool (http://tools.iedb.org/tcrmatch/) that takes TCR β-chain CDR3 sequences as an input, identifies TCRs with a match in the IEDB, and reports the specificity of each match. We anticipate that this tool will provide new insights into T cell responses captured in receptor repertoire and single cell sequencing experiments and will facilitate the development of new strategies for monitoring and treatment of infectious, allergic, and autoimmune diseases, as well as cancer.

In Pursuit of Adult Progenitors of Thymic Epithelial Cells.

Peripheral T cells capable of discriminating between self and non-self antigens are major components of a robust adaptive immune system. The development of self-tolerant T cells is orchestrated by thymic epithelial cells (TECs), which are localized in the thymic cortex (cortical TECs, cTECs) and medulla (medullary TECs, mTECs). cTECs and mTECs are essential for differentiation, proliferation, and positive and negative selection of thymocytes. Recent advances in single-cell RNA-sequencing technology have revealed a previously unknown degree of TEC heterogeneity, but we still lack a clear picture of the identity of TEC progenitors in the adult thymus. In this review, we describe both earlier and recent findings that shed light on features of these elusive adult progenitors in the context of tissue homeostasis, as well as recovery from stress-induced thymic atrophy.

Proteasome-Generated cis-Spliced Peptides and Their Potential Role in CD8+ T Cell Tolerance

The human immune system relies on the capability of CD8+ T cells to patrol body cells, spot infected cells and eliminate them. This cytotoxic response is supposed to be limited to infected cells to avoid killing of healthy cells. To enable this, CD8+ T cells have T Cell Receptors (TCRs) which should discriminate between self and non-self through the recognition of antigenic peptides bound to Human Leukocyte Antigen class I (HLA-I) complexes—i.e., HLA-I immunopeptidomes—of patrolled cells. The majority of these antigenic peptides are produced by proteasomes through either peptide hydrolysis or peptide splicing. Proteasome-generated cis-spliced peptides derive from a given antigen, are immunogenic and frequently presented by HLA-I complexes. Theoretically, they also have a very large sequence variability, which might impinge upon our model of self/non-self discrimination and central and peripheral CD8+ T cell tolerance. Indeed, a large variety of cis-spliced epitopes might enlarge the pool of viral-human zwitter epitopes, i.e., peptides that may be generated with the exact same sequence from both self (human) and non-self (viral) antigens. Antigenic viral-human zwitter peptides may be recognized by CD8+ thymocytes and T cells, induce clonal deletion or other tolerance processes, thereby restraining CD8+ T cell response against viruses. To test this hypothesis, we computed in silico the theoretical frequency of zwitter non-spliced and cis-spliced epitope candidates derived from human proteome (self) and from the proteomes of a large pool of viruses (non-self). We considered their binding affinity to the representative HLA-A*02:01 complex, self-antigen expression in Medullary Thymic Epithelial cells (mTECs) and the relative frequency of non-spliced and cis-spliced peptides in HLA-I immunopeptidomes. Based on the present knowledge of proteasome-catalyzed peptide splicing and neglecting CD8+ TCR degeneracy, our study suggests that, despite their frequency, the portion of the cis-spliced peptides we investigated could only marginally impinge upon the variety of functional CD8+ cytotoxic T cells (CTLs) involved in anti-viral response.

Regulation of Gastrointestinal Immunity by Metabolites.

The gastrointestinal tract contains multiple types of immune cells that maintain the balance between tolerance and activation at the first line of host defense facing non-self antigens, including dietary antigens, commensal bacteria, and sometimes unexpected pathogens. The maintenance of homeostasis at the gastrointestinal tract requires stringent regulation of immune responses against various environmental conditions. Dietary components can be converted into gut metabolites with unique functional activities through host as well as microbial enzymatic activities. Accumulating evidence demonstrates that gastrointestinal metabolites have significant impacts on the regulation of intestinal immunity and are further integrated into the immune response of distal mucosal tissue. Metabolites, especially those derived from the microbiota, regulate immune cell functions in various ways, including the recognition and activation of cell surface receptors, the control of gene expression by epigenetic regulation, and the integration of cellular metabolism. These mucosal immune regulations are key to understanding the mechanisms underlying the development of gastrointestinal disorders. Here, we review recent advancements in our understanding of the role of gut metabolites in the regulation of gastrointestinal immunity, highlighting the cellular and molecular regulatory mechanisms by macronutrient-derived metabolites.

Immunotherapy Sensitivity of Mismatch Repair-Deficient Cancer: Mutation Load Is Not Enough

Abundant neoantigens are considered responsible for the immunotherapy sensitivity of mismatch repair-deficient (MMRd) cancers. In this issue of Cancer Cell, two papers show that MLH1 mismatch repair gene loss promotes cGAS-STING activation, interferon secretion, and Tcell priming. This may be essential for the high immunotherapy sensitivity in MMRd cancer.

Potential benefit of β-glucans as adjuvant therapy in immuno-oncology: a review.

Fungal compounds have long been used for centuries as food supplements. β-glucans have been identified as the most interesting molecules with beneficial effects in several chronic diseases. In vitro studies have shown that they are able to elicit the immune cells maturation and activation with the result of an increased release of proinflammatory cytokines and chemokines and a stimulation of anti-bacterial activity of macrophages and neutrophils. As β-glucans enhance pathogen elimination through non-self antigens identification, they can also direct immune response against tumor cells. These compounds also stimulate the activity on adaptive immune cells and they have been regarded as biological response modifiers. In this way, β-glucans can be exploited as adjuvant cancer therapy, in particular by a synergic action with chemotherapy or immunotherapy. In the immuno-oncology era, the need is to identify innovative drugs that can simultaneously target and inhibit different biological processes relevant for cancer cells survivors. Recent clinical studies showed promising results about the combination of β-glucans and immune checkpoint inhibitors for patients affected by different solid tumors. This review aims to investigate molecular mechanisms of action of β-glucans and is focused on their application in clinical practice as immune-adjuvants for treatment of cancer patients.

T cell Tolerance in Early Life.

T cell-mediated immune tolerance is a state of unresponsiveness of T cells towards specific self or non-self antigens. This is particularly essential during prenatal/neonatal period when T cells are exposed to dramatically changing environment and required to avoid rejection of maternal antigens, limit autoimmune responses, tolerate inert environmental and food antigens and antigens from non-harmful commensal microorganisms, promote maturation of mucosal barrier function, yet mount an appropriate response to pathogenic microorganisms. The cell-intrinsic and cell extrinsic mechanisms promote the generation of prenatal/neonatal T cells with distinct features to meet the complex and dynamic need of tolerance during this period. Reduced exposure or impaired tolerance in early life may have significant impact on allergic or autoimmune diseases in adult life. The uniqueness of conventional and regulatory T cells in human umbilical cord blood (UCB) may also provide certain advantages in UCB transplantation for hematological disorders.