Major Histocompatibility Complex Research Articles

Accurate identification of the interactions between T-cell receptors (TCRs) and antigenic epitopes presented by major histocompatibility complex (MHC) molecules is fundamental to advancing cancer immunotherapy. Nevertheless, predictive modeling of TCR-epitope binding remains challenging, as existing models struggle to generalize to unseen epitopes while often overlooking key physicochemical properties governing immune recognition. Here, a biologically informed vision-guided deep learning framework (DAISY) is proposed for robust and interpretable TCR-epitope binding prediction. DAISY integrates hierarchical physicochemical features via a biologically inspired Condition-Adaptive Fusion module, jointly modeling residue-level spatial interactions and global biochemical context. DAISY consistently outperforms state-of-the-art models across four generalization scenarios, notably improving ROC-AUC by 11% and PR-AUC by 16% over the strongest competitor in the most challenging Unseen-Pair setting. DAISY also offers intuitive interpretability by localizing interaction-relevant residues via Score-CAM visualizations. Furthermore, its computational predictions are bridged to key immunological and clinical outcomes, demonstrating utility in correlating with T-cell clonal expansion, identifying functional TCRs, and robustly forecasting patient survival. Together, DAISY can serve as a powerful tool for broad translational immunology and introduces a scalable modeling paradigm for next-generation immunemodeling.

Abstract Chemical communication is the most ancient and widespread form of communication. In many species, specialised structures called scent glands have evolved to facilitate this communication. These glands vary considerably among species in structure, size, body location and the composition of their secretions. Histological analysis is therefore required to confirm the presence of scent glands, identify secretion types and assess potential roles of the immune system and microbiota in modifying secretions. Here, we investigated the distribution and structure of scent glands in the banded mongoose ( Mungos mungo ), a cooperatively breeding, group‐living mammal. We found that individuals possess two large (1.5 cm diameter) anal glands, each consisting of a central sac surrounded by glandular tissue. This in turn is surrounded by a layer of striated muscle, which likely facilitates the deposition of relatively large quantities of odorous chemicals when engaging in deliberate scent marking behaviour. The glands are lined by two different types of epithelia (keratinised and non‐keratinised) which may impact how immune genes such as the major histocompatibility complex (MHC) affect the microbiome of the glands, and therefore, the chemicals that are secreted during scent marking. Additionally, we reveal a previously unidentified small (0.75 mm in length) scent gland in the cheek, which may be used for scent marking. We provide evidence that banded mongooses may use their chin and abdomen for scent rubbing, as these regions are often rubbed in odorous substances, but we found no evidence of specialised scent glands in these areas. Our findings highlight the importance of integrating anatomical, behavioural and biochemical approaches to understand the mechanisms and purposes of scent communication. This study serves as a foundation for future research on the interplay between scent marking and rubbing behaviours, and the role of immune genes and microbiota in shaping chemical communication in banded mongooses and other mammalian species.

No currently licensed vaccine reliably prevents pulmonary tuberculosis (TB), a leading cause of infectious disease mortality. Developing effective new vaccines requires identifying which Mycobacterium tuberculosis (Mtb) proteins are presented on major histocompatibility complex class II (MHC-II) by infected human phagocytes (target cells) and defining their capacity for recognition by CD4+ T cells. Vaccine designs must elicit T cell responses recognizing the same peptide-MHC complexes presented by infected cells. Although many human CD4+ T cell Mtb epitopes have been described, presentation on MHC-II by infected cells in most cases has not been directly evaluated. Using mass spectrometry (MS), we demonstrated that Mtb type VII secretion system (T7SS) substrates are enriched in the MHC-II repertoire of Mtb-infected human monocyte-derived phagocytes and that many of these antigens are immunogenic in people with prior evidence of Mtb infection. We next used MS to guide TB messenger RNA (mRNA) vaccine design, increasing the presentation of target MHC-II epitopes by orders of magnitude by incorporating design features that mirror aspects of antigen presentation dynamics in infected phagocytes. Our results provide a strategy for TB vaccine design that is guided by bottom-up unbiased discovery. Our approach combines targeted evaluation of antigen presentation in human cells paired with rapid iterative testing of mRNA vaccine designs to optimize antigen presentation before animal studies or human clinical trials.

Background: Cardiac cell therapy with human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) is an emerging strategy to treat myocardial infarction (MI), but long-term immunogenicity of the allogeneic transplantation is unknown. Seeking to achieve long-term engraftment without harsh immunosuppression, we transplanted allogenic CMs differentiated from rhesus macaque induced PSCs (iPSCs) into major histocompatibility complex (MHC)-mismatched rhesus recipients. Methods: A survey was conducted to assess cardiologists’ perceptions about hPSC-CM therapy and immunosuppression. Allogeneic iPSCs from a male rhesus macaque ( Macaca mulatta ) were differentiated into highly enriched cardiomyocytes (riPSC-CMs). 200×10 6 riPSC-CMs were transplanted into 16 MHC-mismatched rhesus recipients with or without MI. Immune modulating interventions included genetically deleting β2-microglobulin (β2M) to create MHC class I-deficient allogeneic CMs, as well as testing four steroid-sparing immunosuppression regimens to determine the minimal immunosuppression required to support long-term engraftment. Results: The majority of cardiologists are likely to offer hPSC-CM therapy to their post-MI patients but only if no or weak chronic immunosuppression is required (Fig. 1). In the absence of immunosuppression, MHC-mismatched riPSC-CM allografts survived for two weeks without significant rejection but were fulminantly rejected by eight weeks (Fig. 2). β2M knockout and resulting MHC I-deficiency did not prevent rejection. Single-agent immunosuppression with abatacept (ABT) or tacrolimus (TAC) led to severe rejection. Mycophenolate mofetil (MMF) combined with TAC also resulted in severe rejection. In contrast, a combination of TAC + ABT supported four of five transplanted grafts for 16 weeks without significant cellular rejection, with a fifth heart showing focal moderate rejection (Fig. 3). Conclusions: A minimal chronic immunosuppression regimen is necessary to translate hPSC-CM therapy. Mismatched allogeneic cardiomyocyte cell therapy is less immunogenic than orthotopic heart transplantation, and graft rejection can be prevented using low intensity immunosuppression with TAC + ABT. Immune-engineering to prevent immunoreactivity will require more than MHC I deletion alone.

Background Cavernous sinus tuberculosis is an extremely rare manifestation of central nervous system tuberculosis in children, with only two cases reported worldwide. It can mimic malignancy or other inflammatory conditions. Its occurrence in children with primary immunodeficiency, particularly major histocompatibility complex (MHC) class II deficiency, has not yet been described. Case report We report an 11-year-old girl with a history of recurrent infections and chronic otitis media. She presented with right orbital swelling, severe headaches, and exophthalmos. Imaging revealed an extensive mass in the sinonasal and orbital regions, extending to the skull base and cavernous sinus. A computed tomography-guided biopsy and histopathology, supported by PCR testing for Mycobacterium tuberculosis , confirmed extensive orbital and cervicofacial tuberculosis. An immunological evaluation and genetic analysis revealed familial MHC class II deficiency. The patient received anti-tuberculosis therapy [isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) followed by isoniazid and rifampin (HR)], leading to clinical and radiological improvement. She continues with intravenous immunoglobulin replacement therapy every 21 days while awaiting a bone marrow transplantation. Conclusions This case highlights the importance of considering tuberculosis in atypical cavernous sinus lesions in children, especially in endemic regions. Severe or unusual infections should prompt evaluation for underlying immunodeficiency.

Targeted therapies for NRAS-mutant melanoma remain an unmet clinical need. Here, we demonstrate that RMC-7977, a preclinical RAS(ON) multi-selective inhibitor representative of the investigational agent daraxonrasib (RMC-6236), was able to elicit potent antitumor immune responses across multiple NRAS-mutant melanoma models. Treatment with RMC-7977 led to rapid tumor regressions driven by inhibition of MAPK signaling, upregulation of major histocompatibility complex (MHC) and PD-L1 proteins, and enhanced infiltration of CD4⁺ and CD8⁺ T cells. Complete responses were dependent on adaptive immunity, as both CD4⁺ and CD8⁺ T cells were essential for extended survival. Resistance to treatment was marked by reduced T-cell infiltration, loss of MHC class I expression, and expansion of myeloid-derived suppressor cells. Combining RMC-7977 with anti-PD-1 boosted cytotoxic T-cell infiltration, reprogrammed myeloid cells toward an antigen-presenting phenotype, and improved survival in models resistant to PD-1 blockade. Consistent with these preclinical data, objective clinical responses were observed in two NRAS-mutant melanoma patients treated with daraxonrasib in an ongoing Phase I/Ib clinical trial. Together, these data support the continued clinical evaluation of RAS(ON) multi-selective inhibitors for the treatment of NRAS-mutant melanoma.

Among mouse models of neurological disease, Theiler’s murine encephalomyelitis virus (TMEV) provides a unique platform by using a naturally occurring viral trigger, paralleling the role of infections like Epstein–Barr virus in multiple sclerosis (MS). Just as not all individuals with predisposing viral infections develop the same neurological disease, not all mouse strains develop the same diseases following TMEV infection, so susceptibility is dictated by genetic background. For example, certain sets of alleles, called haplotypes, of the major histocompatibility complex (MHC) region have been associated with susceptibility to TMEV-induced demyelination (TVID) and MS. However, our previous work revealed that these MHC susceptibility haplotypes are not the sole contributors to TMEV-induced diseases in all mice. We infected mice from the genetically diverse Collaborative Cross (CC), a resource designed to reflect human population-level genetic variation. All 15 CC strains tested exhibited some form of neurological phenotype or CNS lesion following TMEV infection. However, chronic radiculoneuropathy characterized by axonal degeneration with myelin loss was observed in the CNS of only two strains, CC002 and CC023, which had markedly different immune responses and clinical profiles throughout the course of infection. Moreover, the pathology seen in CC002 and CC023 was not the same as what is typically seen in TVID. We used previous results from RNA sequencing of the hippocampus and spinal cord to test our hypothesis that myelin loss in these strains resulted from the convergent biological effects of multiple genetic risk variants, many previously unassociated with TMEV-induced diseases. These findings identify novel genetic targets and demonstrate the utility of genetically diverse models for uncovering complex neuroimmune interactions.

Introduction: The Forkhead box O (FOXO) transcription factor FOXO3 plays a pivotal role in longevity, as single nucleotide polymorphisms (SNPs) in FOXO3 are associated with healthy aging in diverse human populations. Moreover, the FOXO3 longevity genotype increases lifespan only in individuals at risk for cardiometabolic disease, suggesting a protective mechanism played by FOXO3 against cardiac stress. Hypothesis: To test whether FOXO3+ cardiac fibroblasts are inhibiting inflammation in the myocardium and in right ventricle (RV) dysfunction upon pulmonary arterial hypertension (PAH). Methods: Fibroblast-specific Foxo3 knock-out (Foxo3-FB KO ) mice were subjected to pulmonary artery banding (PAB) for 35 days. Right heart ventricle (RV) function was measured by echocardiography and MRI. Cardiac immune composition was defined by single cell RNA-seq on CD45+ cells, immunohistochemistry and FACS analysis. Levels of cytokines were determined by cytokine array. Results: Here we show that conditional deletion of Foxo3 in cardiac fibroblasts leads to up-regulation of major histocompatibility complex type 1 (MHC-I) genes, together with a change in the immune composition of the heart. Foxo3-FB KO hearts display increased numbers of macrophages with high levels of MHC type 2 (MHC-II hi ), increased recruitment of CD8+ T cells and increased expression of cytokines such as IL-1α, IL-1β and IL-17. In spite of this pro-inflammatory signature, Foxo3-FB KO hearts show no functional phenotype at the baseline. However, upon PAB, Foxo3-FB KO mice display aberrant RV remodeling with increased cardiomyocyte hypertrophy and reduced RV ejection fraction. This severe phenotype is associated to higher expression of MHC-I and reduced recruitment of MHC-II hi macrophages. Importantly, FOXO3 is down-regulated in cardiac fibroblasts of patients with decompensated RV hypertrophy due to PAH, and in two different animal models of PAH (monocrotaline rats and PAB mice), indicating a protective role of FOXO3 against RV maladaptive remodeling. Conclusions: We found that inhibition of FOXO3 in cardiac fibroblasts at late stages of RV remodeling leads to activation of MHC-I antigen presentation genes and recruitment of pro-inflammatory T cells which might further exacerbate maladaptive remodeling via increased cytotoxicity. In conclusion, we describe novel protective functions for FOXO3 in RV remodeling and in cardiac immune composition, with important implications for PAH-induced cardiac disease.

Abstract There is evidence that allergic diseases are associated with carcinogenesis. According to translational and epidemiological data, it appears that different cancer types yield different associations. We investigated the relationship between allergic diseases and 28 cancers by Mendelian randomization. Quantitative trait locus analysis was utilized to determine genes expressed in kidney tissue that were affected by allergy-related loci. We further explored the underlying molecular mechanism between allergic diseases and renal cell carcinoma (RCC) with bioinformatics. Of the 28 cancers, evidence suggested that allergies specifically suppressed kidney cancer. Seventy single nucleotide polymorphisms associated with allergic diseases affected the expression of 134 genes in kidney tissue. These 134 genes were enriched in immune-related pathways represented by the major histocompatibility complex class II antigen presentation pathway. Among them, seven core genes were significantly positively correlated with T helper 2 cells. Allergic diseases specifically suppressed RCC through multiple immune pathways. Among them, the major histocompatibility complex class II antigen presentation pathway and T helper 2 cells were the most critical. Our study sheds light on the underlying mechanisms of allergic diseases and RCC and provides therapeutic targets for RCC.

To mount a robust and durable immune response, the antigen in a vaccine must be processed efficiently in the appropriate intracellular compartment. Here, we report an approach for optimizing the antigen processing pathway and efficiency by using the modular design of spherical nucleic acid (SNA) nanostructures. We utilized the substrate specificity of endoplasmic reticulum aminopeptidase1 (ERAP1), a protease known to generate major histocompatibility complex class I (MHC I) epitopes in the endoplasmic reticulum, to design two ERAP1-responsive peptide linkers (EPLs). The peptide linkers append the peptide antigen onto the SNAs to bias the processing pathway toward ERAP1 and to vary the antigen processing efficiency. The two EPLs varied ERAP1 antigen processing efficiency by 10-fold. Subsequently, the EPLs increased colocalization of the antigen with ERAP1 by up to ca. 58% when compared to an SNA that did not employ this linker. The EPL that drove more efficient cleavage, augmented antigen surface presentation by 30%, ex vivo CD8+ T cell proliferation by fivefold, and in vivo generation of proinflammatory and effector memory CD8+ T cells by 5% and 18%, respectively. Furthermore, the more efficiently processed EPL-containing SNA resulted in a 2.5-fold more effective inhibition of E.G7-OVA lymphoma tumors in vivo. Taken together, these findings underscore the importance of the deliberate and rational design of vaccine structures to spatially bias antigen processing and elevate its processing efficiency to augment immune stimulation.

MHC Matchmaker: An In Silico Based Algorithm to Analyze Cross-species NHP, Pig, and Human MHC Compatibility on the Amino Acid Level.

Analysis of antiviral functions, differences and apoptotic effects of two novel MHC-Iα genotypes in orange-spotted grouper (Epinephelus coioides).

Huaier overcomes tumor-induced immunosuppression in colorectal cancer by activating MHC I and CD8+ T cells.

The aryl hydrocarbon receptor inhibits antigen presentation to promote progression of pancreatic ductal adenocarcinoma.

The chicken major histocompatibility complex (MHC) represents a "minimal essential MHC" consisting of classical class I (BF) and class II (BL) molecules that present peptides to CD8+ cytotoxic and CD4+ helper T cells, respectively. Class I molecules, primarily encoded by the BF2 gene, are central to immune responses against pathogens. Moreover, these molecules show enormous genetic diversity driven by a molecular arms race with pathogens that determines peptide binding to the polymorphic α1 and α2 domains. Genotyping tools such as the 90-single nucleotide polymorphism (SNP) panel for the MHC-B region (BSNP) and the LEI0258 microsatellite marker have revealed MHC diversity in chickens but do not capture the variation within the α1 and α2 domains. In this study, six populations of Korean native chickens (KNC) were analyzed to assess BF2 gene diversity in individuals homozygous for both the BSNP panel and LEI0258 marker. Two standard BF2 alleles, B06 and B09, were identical while seven additional haplotypes showed high similarity to those found in KNC samples. A total of 30 novel SNPs were identified, with over half located in peptide-binding regions. Most variants overlapped with previously reported data from polymerase chain reaction (PCR) and next-generation sequencing (NGS), leading to the identification of four unique BF2 alleles in KNC. There was no clear relationship among BSNP, the LEI0258 marker, and the BF2 gene, but individuals homozygous for the first two markers also had a homozygous BF2 region. These findings provide insights into MHC diversity and immune potential in KNC populations, supporting conservation and breeding strategies for enhanced disease resistance. Key points •LEI0258 marker and BSNP haplotypes are good indicators of BF2 gene homozygosity. •Unique BF2 alleles from the KNC lines indicate high genetic diversity that can be used for selective breeding and conservation to enhance diseaseresistance.

DNA methylation landscapes of HIV controllers: an epigenome-wide association study.

Microsatellite stable (MSS) colorectal cancers (CRCs), in contrast to microsatellite instability-high (MSI-H) CRCs, have few mutations and are insensitive to immune checkpoint blockade (ICB). CRCs treated with targeted agents often acquire a high number of genomic alterations at progression. We asked if targeted therapy could be used to generate a high tumor mutational burden (TMB) in MSS CRC and sensitize these tumors to ICB. In patients with MSS metastatic CRC treated with targeted therapy, we evaluated baseline and progression TMB and response to ICB for patients whose tumors developed high TMB. We determined types of alterations, mutational signatures, neoantigenicity, and clonality associated with emergent genomic alterations in cases of acquired high TMB. Among 26 cases, nine acquired high TMB at progression. Three of these patients received ICB but none had a response. In the TMB-high cases, we found no induction of tumor-infiltrating lymphocytes or programmed death-ligand 1 expression. Acquired genomic alterations consisted predominantly of single nucleotide variants, were enriched for single-base substitution 17a/b mutational signature, and did not enhance predicted major histocompatibility complex class I binding. TMB was higher in plasma, driven by highly subclonal acquired alterations, compared to tissue samples which harbored few resistance alterations. A substantial number of MSS CRCs acquire high TMB following targeted therapy. However, this change is not associated with sensitization to ICB. The high TMB is due to subclonal alterations unique to individual disease sites that are inadequate to elicit a robust antitumor immune response.

Streptococcus suis (S. suis) is an important zoonotic pathogen that causes severe disease in both humans and pigs, leading to substantial economic losses in the swine industry. Extracellular vesicles (EVs), as critical mediators of host–pathogen interactions, play key roles in bacterial virulence and disease progression. This study aimed to investigate the biological properties of S. suis EVs and elucidate their role in the bacterium’s pathogenesis. We isolated and characterized S. suis EVs, which were found to contain diverse protein molecules. EVs were efficiently internalized by mammalian cells, and concentrations below 50 μg/mL did not affect cell viability. Following uptake, EVs suppressed the production of key pro-inflammatory cytokines (TNF-α, IL-1β, and IL-8) by modulating macrophage metabolism. They also downregulated the expression of major histocompatibility complex class II (MHC-II) and adhesion molecules (VCAM-1 and ICAM-1) during subsequent infections, potentially impairing macrophage-mediated clearance. In addition, EVs served as vectors for efficient cargo delivery and facilitated S. suis adhesion to and invasion of endothelial cells. In infection models, EVs markedly enhanced lethality in Galleria mellonella larvae and promoted tissue colonization in murine models. These findings suggest that S. suis EVs are key mediators of host–pathogen interactions, contributing to colonization and disease pathogenesis. Moreover, they offer novel insights and potential strategies for the prevention and control of S. suis infections.

The role of CD8+ tissue-resident memory T (CD8+ TRM) in inflammation is well established. However, the mechanisms by which CD8+ TRM cells are activated in tissues have remained elusive. Here, we show that Leucine zipper-like transcription regulator 1 (LZTR1), a substrate adaptor for cullin3 (CUL3) ubiquitin ligase complex, regulates CD8+ TRM activation and proliferation in cutaneous and colonic epithelia through modulation of major histocompatibility complex class I (MHC-I) expression in an NF-κB1-dependent manner. Mechanistically, LZTR1 modulates MHC-I transcription by regulating co-translational biogenesis of NF-κB1 (p50) in a ubiquitination-independent but proteasome-dependent manner through direct binding with ribosome and proteasome. Loss of LZTR1 leads to suppression of CD8+ TRM activation and proliferation and decreased production of IL-17A with blunting of inflammatory responses in both cutaneous and gut epithelia in vivo. In summary, these data identify LZTR1 as a novel regulator of CD8+ TRM function and provide insights into the mechanisms that drive and maintain CD8+ T-cell responses in epithelial-associated autoimmune diseases.

Acute rejection (AR) remains a major determinant of renal allograft outcomes, with the major histocompatibility complex (MHC) playing a pivotal role in its pathogenesis. Although immunosuppressive therapies have advanced, their reliance on high doses and lifelong administration increases the risks of infections, malignancies, and other serious complications. Normothermic machine perfusion (NMP) has emerged as a valuable tool in clinical transplantation, enabling organ preservation, functional assessment, and therapeutic intervention. Integrating NMP with genetic engineering approaches to modulate donor kidney MHC expression may offer a novel strategy for preventing AR. We synthesized cholesterol-modified small interfering RNA targeting B2m and Ciita (siB2m-Chol and siCiita-Chol) and set cholesterol-modified negative control small interfering RNA (siNC-Chol) as control. Interfering with MHC expression in transplanted kidneys using NMP combined with siB2m-Chol and siCiita-Chol pretreatment of donor kidneys to prevent AR of posttransplant allografts, we evaluated the efficacy of this approach by assessing postoperative survival, renal function, histological features, and inflammatory responses. NMP combined with siB2m-Chol and siCiita-Chol significantly reduced MHC expression on postoperative day 3, improved allograft function, and prolonged recipient survival. By postoperative day 7, pathological damage was reduced, and T cells, macrophages, B cells, donor-specific antibodies, and inflammatory cytokine production were markedly lower in treated grafts compared with the siNC-Chol control group. These findings demonstrate that ex vivo NMP effectively delivers cholesterol-modified small interfering RNA to renal grafts, substantially downregulating both MHC class I and II expression and consequently attenuating AR.