A class II MHC-targeted vaccine elicits immunity against SARS-CoV-2 and its variants

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 100 million infections and millions of deaths. Effective vaccines remain the best hope of curtailing SARS-CoV-2 transmission, morbidity, and mortality. The vaccines in current use require cold storage and sophisticated manufacturing capacity, which complicates their distribution, especially in less developed countries. We report the development of a candidate SARS-CoV-2 vaccine that is purely protein based and directly targets antigen-presenting cells. It consists of the SARS-CoV-2 Spike receptor-binding domain (SpikeRBD) fused to an alpaca-derived nanobody that recognizes class II major histocompatibility complex antigens (VHHMHCII). This vaccine elicits robust humoral and cellular immunity against SARS-CoV-2 and its variants. Both young and aged mice immunized with two doses of VHHMHCII-SpikeRBD elicit high-titer binding and neutralizing antibodies. Immunization also induces strong cellular immunity, including a robust CD8 T cell response. VHHMHCII-SpikeRBD is stable for at least 7 d at room temperature and can be lyophilized without loss of efficacy.

The Association of HLA-DQ2 with Celiac Disease

DQ2 is a surface receptor of class II MHC exposed on APC immune-competent cells. Its function is to recognize non-self-antigens and present them to CD4+ T-helper lymphocytes, which activate cytokine <21> production and control antibody production and cell response. The activation of T lymphocytes by peptides derived from gluten proteins and the production of antibodies directed against tTG in tissues where it is localized is the basis of the etiopathogenesis of celiac disease (CD). CD is frequently associated with the presence of specific HLA system genes encoding heterodimers DQ2 and DQ8, identifiable by the DQA1*0501/DQB1*0201 or DQA1*0501/DQB1*0202 and DQB1*0302 alleles. DQ2 is also associated with genetic, endocrinological and neurological diseases such as: type 1 diabetes, thyroiditis, pancreatitis and multiple sclerosis. Interactions between DQ2 and T lymphoma have also been demonstrated. The correlation between autoimmune diseases in patients with CD and therefore DQ2 is much more frequent than in healthy subjects.

Machine learning optimization of peptides for presentation by class II MHCs

T cells play a critical role in cellular immune responses to pathogens and cancer and can be activated and expanded by MHC-presented antigens contained in peptide vaccines. We present a machine learning method to optimize the presentation of peptides by class II MHCs by modifying their anchor residues. Our method first learns a model of peptide affinity for a class II MHC using an ensemble of deep residual networks, and then uses the model to propose anchor residue changes to improve peptide affinity. We use a high throughput yeast display assay to show that anchor residue optimization improves peptide binding. Supplementary information: Supplementary data are available at Bioinformatics online.

Analysis of Genetic Variability in the Caprine Class II MHC CLA DRB3.2(Cahi DRB3.2) gene locus of the Sangamneri goat breed of India

The objective of this study was to assess the genetic variability present across the Class II MHC DRB 3.2 gene locus in the Sangamneri goat breed of India. Sixty three single nucleotide variations were observed in CLA-DRB3.2 gene of eleven Sangamneri animals. Sixteen haplotypes with Haplotype diversity of 0.974 were found. Besides the snp(s) having two alleles, both triple and tetra allelic single nucleotide variations were present. Thus, the Class II DRB 3.2 gene of the Sangamneri goat breed animals (CLA-DRB3.2/ Cahi DRB3.2) was exhibiting a very high degree of genetic polymorphism. Of the sixty three single nucleotide variations, fifty variations were non-synonymous i.e. they resulted in a change in the corresponding amino acid encoded by the triplet codon in which they were existing. Both conservative and non-conservative amino acid changes were observed to occur. Rich diversity of the DRB3.2 gene reflected well on the ability of the Sangamneri animals to survive in the harsh climatic condition(s), exposed to all kinds of pathogen(s) existing in the environment.

Single domain antibody-antigen adducts that target Class II MHC induce antigen-specific tolerance

The association of autoimmune diseases with particular allelic variants of Class II MHC (MHCII) products implicates presentation of the offending self-antigen(s) to T cells. Antigen presenting cells are tolerogenic when they encounter antigen under non-inflammatory conditions. Manipulation of antigen presentation would therefore be a possible intervention to induce antigen-specific tolerance. We show that, under non-inflammatory conditions, systemic administration of a single dose of a nanobody that recognizes MHCII (VHH MHCII) conjugated to the relevant self-antigen affords long-lasting protection against induction of experimental autoimmune encephalitis (EAE), type 1 diabetes (T1D), and rheumatoid arthritis (RA). Co-administration of the VHH MHCII-antigen adduct together with dexamethasone, conjugated to VHH MHCII via a cleavable linker, not only halted progression of established EAE in symptomatic mice but even reverted the severity of EAE, establishing this approach as a potential means of treating autoimmune conditions.

MHC Sınıf I ve MHC Sınıf II Gen Düzenlenmesi

Introduction: Peptides obtained by processing intracellular and extracellular antigens are presented to T cells to stimulate the immune response. This presentation is made by peptide receptors called major histocompatibility complex (MHC) molecules. The regulation mechanisms of MHC molecules, which have similar roles in the immune response, especially at the gene level, have significant differences according to their class. Objective: Class I and class II MHC molecules encoded by MHC genes on the short arm of the sixth chromosome are peptide receptors that stimulate T cell response. These peptides, which will enable the recognition of the antigen from which they originate, are loaded into MHC molecules and presented to T cells. Although the principles of loading and delivering peptides are similar for both molecules, the peptide sources and peptide loading mechanisms are different. In addition, class I molecules are expressed in all nucleated cells while class II molecules are expressed only in Antigen Presentation Cells (APC). These differences; It shows that MHC class I is not expressed by exactly the same transcriptional mechanisms as MHC class II. In our article, we aimed to compare the gene expressions of both classes and reveal their similarities and differences. Discussion and Conclusion: A better understanding of the transcriptional mechanisms of MHC molecules will reveal the role of these molecules in diseases more clearly. In our review, we discussed MHC gene regulation mechanisms with presence of existing informations, which is specific to the MHC class, for contribute to future research. Keywords: MHC class I, MHC class II, MHC gene regulation, promoter, SXY module, transcription

Suppression of liver transplant rejection by anti-donor MHC antibodies via□ depletion of donor immunogenic dendritic cells

Background We previously found two distinct passenger dendritic cell (DC) subsets in the rat liver that played a central role in the liver transplant rejection. In addition, tolerance-inducing protocol, donor-specific transfusion (DST), triggered systemic polytopical production of depleting alloantibodies to donor class I MHC antigen (DST-antibodies). Methods We examined the role of DST-antibodies in the trafficking of graft DC subsets and the alloresponses in a rat model. We also examined an anti-donor class II MHC (MHCII) antibody that recognizes donor DCs more selectively. Results Preoperative transfer of DST-antibodies and DST pretreatments eliminated all passenger leukocytes, including both DC subsets and depleted the sessile DCs in the graft to ~20% of control. The CD172a +CD11b/c + immunogenic subset was almost abolished. The intrahost direct or semi-direct allorecognition pathway was successfully blocked, leading to a significant suppression of the CD8 + T-cell response in the recipient lymphoid organs and the graft with delayed graft rejection. Anti-donor MHCII antibody had similar effects without temporary graft damage. Although DST pretreatment had a priming effect on the recipient Treg proliferative response, DST-primed sera and the anti-donor MHCII antibody did not. Conclusion DST-antibodies and anti-donor MHCII antibodies could suppress the CD8 + T-cell-mediated liver transplant rejection by depleting donor immunogenic DCs, blocking the direct or semi-direct pathway of allorecognition. Donor MHCII-specific antibodies may be applicable as a selective suppressant of anti-donor immunity for clinical liver transplantation without the cellular damage of donor MHCII – graft cells and recipient cells.

P02.02 Generating neo- and self-antigen screening libraries for class II HLA presentation

BackgroundThe identification of neo-antigens presented by tumor cells is an essential tool for cancer prevention, diagnosis, and therapy. Current approaches frequently involve mass spectrometric analysis, but these workflows do not concomitantly identify the cognate T-cell receptor. Likewise, TCR functional screens are often limited to a subset of predicted neo-epitopes.Materials and MethodsHere, we present a new method for the generation of an un-biased antigen-presenting library. Due to the genomic instability of tumors, patient-specific libraries will be cloned using random primers, ensuring the cloning of tumor-specific transcribed regions. This approach will not only address class I presentation of intracellular tumor antigens, but is also designed to simultaneously screen for cross-presentation on class II MHC complexes by professional antigen-presenting cells, an increasingly important component of anti-tumor immune responses. To guarantee presentation of genetically encoded antigens on class II MHC complexes, a signal motif for chaperone-mediated autophagy (CMA) is introduced in front of the cDNA sequence. Furthermore, antigens will be processed by the intracellular machinery, avoiding potential restrictions on spliced peptides.ConclusionsOnce established, these libraries can be exploited in high-throughput screens to functionally identify neo-antigens together with their corresponding T-cell receptor.Disclosure InformationV. Pinamonti: Other; Significant; Janssen. N. Felix: Other; Significant; Janssen. J.M. Lindner: Other; Significant; Janssen.