Transmembrane Helices Are an Over-Presented and Evolutionarily Conserved Source of Major Histocompatibility Complex Class I and II Epitopes

Cytolytic T cell responses are predicted to be biased towards membrane proteins. The peptide-binding grooves of most alleles of histocompatibility complex class I (MHC-I) are relatively hydrophobic, therefore peptide fragments derived from human transmembrane helices (TMHs) are predicted to be presented more often as would be expected based on their abundance in the proteome. However, the physiological reason of why membrane proteins might be over-presented is unclear. In this study, we show that the predicted over-presentation of TMH-derived peptides is general, as it is predicted for bacteria and viruses and for both MHC-I and MHC-II, and confirmed by re-analysis of epitope databases. Moreover, we show that TMHs are evolutionarily more conserved, because single nucleotide polymorphisms (SNPs) are present relatively less frequently in TMH-coding chromosomal regions compared to regions coding for extracellular and cytoplasmic protein regions. Thus, our findings suggest that both cytolytic and helper T cells are more tuned to respond to membrane proteins, because these are evolutionary more conserved. We speculate that TMHs are less prone to mutations that enable pathogens to evade T cell responses.

Individual copy number variation and extensive diversity between major MHC-DAB1 allelic lineages in the European bitterling

Polymorphism of the major histocompatibility complex (MHC), DAB1 gene was characterized for the first time in the European bitterling (Rhodeus amarus), a freshwater fish employed in studies of host-parasite coevolution and mate choice, taking advantage of newly designed primers coupled with high-throughput amplicon sequencing. Across 221 genotyped individuals, we detected 1–4 variants per fish, with 28% individuals possessing 3–4 variants. We identified 36 DAB1 variants, and they showed high sequence diversity mostly located within predicted antigen-binding sites, and both global and codon-specific excess of non-synonymous mutations. Despite deep divergence between two major allelic lineages, functional diversity was surprisingly low (3 supertypes). Overall, these findings suggest the role of positive and balancing selection in promotion and long-time maintenance of DAB1 polymorphism. Further investigations will clarify the role of pathogen-mediated selection to drive the evolution of DAB1 variation.

Induction of Donor-Specific Immune Hypo-Responsiveness Across Major Histocompatibility Complex Barriers in Murine Models of Solid Organ Transplant: Repurposing Extracorporeal Photochemotherapy

Recipients of solid organ transplantation (SOT) rely on life-long immunosuppression (IS), which is associated with significant side effects. Extracorporeal photochemotherapy (ECP) is a safe, existing cellular therapy used to treat transplant rejection by modulating the recipient’s own blood cells. We sought to induce donor-specific hypo-responsiveness of SOT recipients by infusing ECP-treated donor leukocytes prior to transplant. To this end, we utilized major histocompatibility complex (MHC) mismatched rodent models of allogeneic cardiac, liver, and kidney transplantation to test this novel strategy. Leukocytes isolated from donor-matched spleens for ECP treatment (ECP-DL) were infused into transplant recipients seven days prior to SOT. Pre-transplant infusion of ECP-DL without additional IS was associated with prolonged graft survival in all models. This innovative approach promoted the production of tolerogenic dendritic cells and regulatory T-cells with subsequent inhibition of T-cell priming and differentiation, along with a significant reduction of donor-specific T-cells in the spleen and grafts of treated animals. This new application of donor-type ECP-treated leukocytes provides insight into the mechanisms behind ECP-induced immunoregulation and holds significant promise in the prevention of graft rejection and reduction in need of global immune suppressive therapy in patients following SOT.

The Salmonella transmembrane effector SteD hijacks AP1-mediated vesicular trafficking for delivery to antigen-loading MHCII compartments

SteD is a transmembrane effector of the Salmonella SPI-2 type III secretion system that inhibits T cell activation by reducing the amounts of at least three proteins – major histocompatibility complex II (MHCII), CD86 and CD97 – from the surface of antigen-presenting cells. SteD specifically localises at the trans -Golgi network (TGN) and MHCII compartments; however, the targeting, membrane integration and trafficking of SteD are not understood. Using systematic mutagenesis, we identify distinct regions of SteD that are required for these processes. We show that SteD integrates into membranes of the ER/Golgi through a two-step mechanism of membrane recruitment from the cytoplasm followed by integration. SteD then migrates to and accumulates within the TGN. From here it hijacks the host adaptor protein (AP)1-mediated trafficking pathway from the TGN to MHCII compartments. AP1 binding and post-TGN trafficking require a short sequence in the N-terminal cytoplasmic tail of SteD that resembles the AP1-interacting dileucine sorting signal, but in inverted orientation, suggesting convergent evolution.

Epithelial MHC class II directs microbiota-specific intestinal immune homeostasis

Dysregulated immune responses to resident microbes promote pathologic inflammation, however, the mechanisms instructing commensal-specific T cells remain poorly understood. Here, we find that non-hematopoietic intestinal epithelial cells (IECs) represent the primary cells expressing major histocompatibility complex (MHC) II at the intestinal host-microbiota interface. Interestingly, epithelial MHCII and commensal-specific CD4+ T cells were concurrently induced by post-natal microbiota colonization, provoking the hypothesis that epithelial MHCII regulates local commensal-specific CD4+ T cells. While MHCII on classical antigen presenting cells directs expansion of antigen-specific CD4+ T cells, loss of IEC-intrinsic MHCII surprisingly led to elevated commensal-specific CD4+ T cells in the intestine. Further, epithelial MHCII expression actively limited accumulation of antigen-specific CD4+ T cells in adult mice. Expansion of commensal-specific Th17 cells was restricted by epithelial MHCII, and remarkably mice lacking epithelial MHCII were highly susceptible to microbiota-triggered inflammation. Collectively, these data indicate that impaired epithelial MHCII-T cell regulation within mucosal tissues alters microbiota-specific immunity and predisposes to chronic inflammation.

Perspectives Concerning Various Symptoms of SARS-CoV-2 Detected Individuals

After exposure to SARS-CoV-2, varying symptoms of COVID-19 ranging from asymptomatic symptoms to morbidity and mortality have been exhibited in each individual. SARS-CoV-2 requires various cellular molecules for penetration into a target host cell. Angiotensin-converting enzyme2 (ACE2) acts as the viral receptor molecule. After attachment, SARS-CoV-2 also requires the transmembrane protease serine-2 (TMPRSS-2) and furin molecules, which serve as co-receptors for penetration into the target cell and for subsequent replication. In the meantime, a major histocompatibility complex (MHC) is required for the induction of adaptive immune cells, especially cytotoxic T cells and helper T cells, to clear the virally infected cells. This perspective review article proposes different aspects to explain the varying symptoms of the individuals who have been exposed to SARS-CoV-2, which relates to the polymorphisms of these involved molecules.

Effect of Ethyl Acetate Fraction of Marsilea crenata Presl. Leaf Extract on Major Histocompatibility Complex Class II Expression in Microglial HMC3 Cell Lines

Phytoestrogens are plant-derived chemical substances that have estrogen-like structures or estrogenic functions. Deficiency of estrogen in human brain causes neuroinflammation characterized by increase of major histocompatibility complex class II (MHC II) expression as a marker of M1 phenotype in microglia. Recent research found phytoestrogen compounds in Marsilea crenata Presl. The aim of this study was to investigate the effect of ethyl acetate fraction of Marsilea crenata Presl. leaf extract in MHC II expression of microglial HMC3 cell lines, for resolution of inflammation and tissue repair. The fractions were given at concentrations of 62.5, 125, and 250 ppm to microglia, that had been previously induced by IFNγ 10 ng for 24 hours to stimulate the cells into M1 phenotype. Genistein as phytoestrogen was given at a concentration of 50 μM as positive control. Expression of MHC II was analyzed using immunocytochemistry method. Result showed reduction in MHC II expression of microglial cells, which indicated the activity of all extracts and, showed that 250 ppm of the fraction showed the strongest effect with MHC II value expression of 148.632 AU, and ED50 of 1,590 ppm. It was concluded from the study, that ethyl acetate fraction of Marsilea crenata Presl. leaves has antineuroinflammation effect.

Genome-wide association study of disease resilience traits from a natural polymicrobial disease challenge model in pigs identifies the importance of the major histocompatibility complex region

Infectious diseases cause tremendous financial losses in the pork industry, emphasizing the importance of disease resilience, which is the ability of an animal to maintain performance under disease. Previously, a natural polymicrobial disease challenge model was established, in which pigs were challenged in the late nursery phase by multiple pathogens to maximize expression of genetic differences in disease resilience. Genetic analysis found that performance traits in this model, including growth rate, feed and water intake, and carcass traits, as well as clinical disease phenotypes, were heritable and could be selected for to increase disease resilience of pigs. The objectives of the current study were to identify genomic regions that are associated with disease resilience in this model, using genome-wide association studies and fine mapping methods, and to use gene set enrichment analyses to determine whether genomic regions associated with disease resilience are enriched for previously published quantitative trait loci (QTL), functional pathways, and differentially expressed genes subject to physiological states. Multiple QTL were detected for all recorded performance and clinical disease traits. The major histocompatibility complex (MHC) region was found to explain substantial genetic variance for multiple traits, including for growth rate in the late nursery (12.8%) and finisher (2.7%), for several clinical disease traits (up to 2.7%), and for several feeding and drinking traits (up to 4%). Further fine mapping identified four QTL in the MHC region for growth rate in the late nursery that spanned the subregions for class I, II, and III, with one SNP in the MHC Class I subregion capturing the largest effects, explaining 0.8 to 27.1% of genetic variance for growth rate and for multiple clinical disease traits. This SNP was located in the enhancer of TRIM39 gene, which is involved in innate immune response. The MHC region was pleiotropic for growth rate in the late nursery and finisher, and for treatment and mortality rates. Growth rate in the late nursery showed strong negative genetic correlations in the MHC region with treatment or mortality rates (-0.62 to -0.85) and a strong positive genetic correlation with growth rate in the finisher (0.79). Gene set enrichment analyses found genomic regions associated with resilience phenotypes to be enriched for previously identified disease susceptibility and immune capacity QTL, for genes that were differentially expressed following bacterial or virus infection and immune response, and for gene ontology terms related to immune and inflammatory response. In conclusion, the MHC and other QTL that harbor immune related genes were identified to be associated with disease resilience traits in a large-scale natural polymicrobial disease challenge. The MHC region was pleiotropic for growth rate under challenge and for clinical disease traits. Four QTL were identified across the class I, II, and III subregions of the MHC for nursery growth rate under challenge, with one SNP in the MHC Class I subregion capturing the largest effects. The MHC and other QTL identified play an important role in host response to infectious diseases and can be incorporated in selection to improve disease resilience, in particular the identified SNP in the MHC Class I subregion.