Major Histocompatibility Complex Class I Molecules Research Articles

IMMU-15. CD74/MIF SIGNALING AXIS DISRUPTION IN BONE MARROW-DERIVED MYELOID CELLS DELAYS MALIGNANT PROGRESSION IN A PRECLINICAL MODEL OF GLIOMA

Abstract INTRODUCTION CD74, a chaperone associated with the major histocompatibility complex class II (MHC-II), plays a crucial role in assembling and transporting MHC-II molecules on the cellular surface. Beyond its physiological function in antigen presentation, CD74 is a negative regulator of inflammation, and its dysregulation is associated with inflammatory disorders and cancer. Notably, tumor stem cells release macrophage migration inhibitory factor (MIF) to trigger CD74 immunosuppressive signaling in tumor-infiltrating immune cells, thereby abrogating CD8+ T cell activation and promoting angiogenesis. While CD74 expression is known in dendritic cells, macrophages and B cells, our recent findings reveal its upregulation in immunosuppressive macrophages within the low-grade glioma (LGG) tumor microenvironment, and its negative correlation with the survival of adolescent and young adult patients with LGG. HYPOTHESIS. We hypothesize that inhibiting CD74/MIF in immunosuppressive myeloid cells may affect tumor progression and prevent malignant transformation (MT) to high-grade glioma (HGG). METHODS To test our hypothesis, we isolated bone marrow cells from immunocompetent RCAS n/tv-a LGG bearing animals, differentiated them into bone marrow-derived myeloid cells (BMDMs), silenced CD74 expression, and co-cultured them with primary CD8+T cells. Moreover, we inhibited CD74/MIF signaling in vivo. RESULTS. Deconvolution analysis of tumor-infiltrating immune cells revealed upregulation of CD74 and its network in myeloid cells during LGG compared to HGG. Silencing CD74 in LGG BMDMs in vitro resulted in the downregulation of genes associated with migration, proliferation, and immunosuppression. The co-culture of LGG CD74KD-BMDMs with CD8+ T cells increased the expression of T cell activation genes. In vivo treatment of LGG mice with MIF inhibitors significantly decreased myeloid cell infiltration in the tumor microenvironment (TME) and prolonged survival. CONCLUSIONS These preclinical studies highlight a role for the CD74/MIF signaling axis in glioma and present a novel immunotherapeutic target to modulate the activity of immunosuppressive myeloid cells in order to delay MT.

PEDV evades MHC-I-related immunity through nsp1-mediated NLRC5 translation inhibition.

Major histocompatibility complex class I (MHC-I) plays crucial roles against viral infections not only by initiating CD8+ T cell immunity but also by modulating natural killer (NK) cell cytotoxicity. Understanding how viruses precisely regulate MHC-I to optimize their infection is important; however, the manipulation of MHC-I molecules by porcine epidemic diarrhea virus (PEDV) remains unclear. In this study, we demonstrate that PEDV infection promotes the transcription of NLRC5, a key transactivator of MHC-I, in several porcine cell lines and in vivo. Paradoxically, no increase in MHC-I expression is observed after PEDV infection both in vitro and in vivo. Mechanistic studies revealed that PEDV infection inhibits the translation of PEDV-elicited NLRC5 mRNA and the expression of downstream MHC-I proteins, without affecting the expression of physiological NLRC5 and MHC-I proteins. Through viral protein screening, we identified PEDV nonstructural protein 1 (nsp1) as the critical antagonist that inhibits NLRC5-mediated upregulation of MHC-I, and the nsp1's inhibitory effect on MHC-I requires the motif of 15 amino acids at its C-terminus. Notably, our results revealed that the cytotoxic ability of NK cells against PEDV-infected cells is similar to that against healthy cells. Collectively, our findings uncover an immune evasion mechanism by which PEDV-infected cells masquerade as healthy cells to evade NK and T cell immunity. This is achieved by targeting NLRC5, a key MHC-I transcriptional regulator, via nsp1.IMPORTANCEPorcine epidemic diarrhea virus (PEDV) is a highly contagious enteric coronavirus that inflicts substantial financial losses on the swine industry. Major histocompatibility complex class I (MHC-I) is a critical factor influencing both CD8+ T cell and natural killer (NK) cell immunity. However, how PEDV manipulates MHC-I expression to optimize its infection process remains largely unknown. In this study, we demonstrate that PEDV's nonstructural protein 1 (nsp1) inhibits virus-mediated induction of MHC-I expression by directly targeting NLRC5, a key MHC-I transactivator. Intriguingly, nsp1 does not reduce physiological NLRC5 and MHC-I expression. This selective inhibition of virus-elicited NLRC5 mRNA translation allows PEDV-infected cells to masquerade as healthy cells, thereby evading CD8+ T cell and NK cell cytotoxicity. Our findings provide unique insights into the mechanisms by which PEDV evades CD8+ T cell and NK cell immunity.

Expansion of MHC-IIB Has Constrained the Evolution of MHC-IIA in Passerines.

The major histocompatibility complex (MHC) is central in adaptive immunity, with the highly polymorphic MHC genes encoding antigen-presenting molecules. Two MHC class II (MHC-II) loci, DA1 and DA2, predate the radiation of extant birds and persist throughout much of the avian phylogeny. Within each locus, the MHC-II molecules are encoded by A-genes (DAA) and B-genes (DAB), which are arranged in A-B dyads. However, in passerines (order Passeriformes), the DA2 locus has been lost, and the ancestral A-B dyad at the DA1 locus has been replaced by a putatively single A-gene (DAA1) and an array of highly polymorphic B-genes (DAB1). In this study, we genotyped the DAA1 gene of 15 passerine species and confirmed that passerines possess just one copy of DAA1. We then compared selection patterns in DAA1 between passerines and nonpasserines and found that exon 2, which encodes the antigen-presenting domain, has been subject to weaker positive selection and stronger negative selection in passerines compared with nonpasserines. Additional comparisons showed that the patterns of selection in the passerine DAA1 gene are unlikely to be related to the loss of the DA2 locus. Instead, our findings suggest that the expansion of DAB1 (MHC-IIB) has imposed an evolutionary constraint on the passerine DAA1 (MHC-IIA) gene. We speculate that this constraint may be the result of each DAA1 chain forming heterodimers with many different DAB1 chains.

Structural basis for mouse LAG3 interactions with the MHC class II molecule I-Ab

The immune checkpoint protein, Lymphocyte activation gene-3 (LAG3), binds Major Histocompatibility Complex Class II (MHC-II) and suppresses T cell activation. Despite the recent FDA approval of a LAG3 inhibitor for the treatment of melanoma, how LAG3 engages MHC-II on the cell surface remains poorly understood. Here, we determine the 3.84 Å-resolution structure of mouse LAG3 bound to the MHC-II molecule I-Ab, revealing that domain 1 (D1) of LAG3 binds a conserved, membrane-proximal region of MHC-II spanning both the α2 and β2 subdomains. LAG3 dimerization restricts the intermolecular spacing of MHC-II molecules, which may attenuate T cell activation by enforcing suboptimal signaling geometry. The LAG3-MHC-II interface overlaps with the MHC-II-binding site of the T cell coreceptor CD4, implicating disruption of CD4-MHC-II interactions as a mechanism for LAG3 immunosuppressive function. Lastly, antibody epitope analysis indicates that multiple LAG3 inhibitors do not recognize the MHC-II-binding interface of LAG3, suggesting a role for functionally distinct mechanisms of LAG3 antagonism in therapeutic development.

MHCI trafficking signal‐based mRNA vaccines strengthening immune protection against RNA viruses

AbstractThe major histocompatibility complex class I (MHCI) trafficking signal (MITD) plays a pivotal role in enhancing the efficacy of mRNA vaccines. However, there was a lack of research investigating its efficacy in enhancing immune responses to RNA virus infections. Here, we have developed an innovative strategy for the formulation of mRNA vaccines. This approach involved the integration of MITD into the mRNA sequence encoding the virus antigen. Mechanistically, MITD‐based mRNA vaccines can strengthen immune protection by mimicking the dynamic trafficking properties of MHCI molecule and thus expand the memory specific B and T cells. The model MITD‐based mRNA vaccines encoding binding receptor‐binding domain (RBD) of SARS‐CoV‐2 were indeed found to achieve protective duration, optimal storage stability, broad efficacy, and high safety.

Gluten-Dependent Activation of CD4+ T Cells by MHC Class II–Expressing Epithelium

Intestinal epithelial cell (IEC) damage is a hallmark of celiac disease (CeD); however, its role in gluten-dependent T-cell activation is unknown. We investigated IEC-gluten-T-cell interactions in organoid monolayers expressing human major histocompatibility complex class II (HLA-DQ2.5), which facilitates gluten antigen recognition by CD4+ T cells in CeD. Epithelial major histocompatibility complex class II (MHCII) was determined in active and treated CeD, and in nonimmunized and gluten-immunized DR3-DQ2.5 transgenic mice, lacking mouse MHCII molecules. Organoid monolayers from DR3-DQ2.5 mice were treated with or without interferon (IFN)-γ, and MHCII expression was evaluated by flow cytometry. Organoid monolayers and CD4+ T-cell co-cultures were incubated with gluten, predigested, or not by elastase-producing Pseudomonas aeruginosa or its lasB mutant. T-cell function was assessed based on proliferation, expression of activation markers, and cytokine release in the co-culture supernatants. Patients with active CeD and gluten-immunized DR3-DQ2.5 mice demonstrated epithelial MHCII expression. Organoid monolayers derived from gluten-immunized DR3-DQ2.5 mice expressed MHCII, which was upregulated by IFN-γ. In organoid monolayer T-cell co-cultures, gluten increased the proliferation of CD4+ T cells, expression of T-cell activation markers, and the release of interleukin-2, IFN-γ, and interleukin-15 in co-culture supernatants. Gluten metabolized by P aeruginosa, but not the lasB mutant, enhanced CD4+ T-cell proliferation and activation. Gluten antigens are efficiently presented by MHCII-expressing IECs, resulting in the activation of gluten-specific CD4+ T cells, which is enhanced by gluten predigestion with microbial elastase. Therapeutics directed at IECs may offer a novel approach for modulating both adaptive and innate immunity in patients with CeD.

Abstract 4105: Immune-modulating vaccines targeting CD73

Abstract Background: To realize the generalizable regulation of the tumor microenvironment (TME), immune-modulating vaccines are developed to target shared antigens expressed by immunosuppressive cells and cancer cells. CD73, also known as ecto-5'-nucleotidase, is a pivotal enzyme in the adenosine metabolic pathway and is expressed on the surface of multiple cancer cells and immunosuppressive cells in the TME. In this study, we aim to develop a CD73-targeting immune modulatory peptide vaccine by predicting antigen sequences, screening immunogenic antigen peptides, and assessing their anti-tumor efficacy and capacity to improve the TME. Methods: The expression level of CD73 on various cancer cell lines were evaluated by flow cytometry. Several online software were used to predict CD73-derived peptides that bind to the mouse MHC-I (major histocompatibility complex class I) molecules. Cells from the draining lymph nodes of healthy mice and peptide-immunized mice were harvested and stimulated by the synthetic peptides in vitro. T cell activation level, IFN-γrelease degree and their cytolytic capability towards cancer cells was measured. CD73-derived peptides were mixed with CpG to treat 4T1 tumor-bearing mice and the changes in the TME were investigated by flow cytometry. The online website (www.camoip.net) was used to analyze the correlation between CD73 expression and patient survival in the TCGA Breast invasive carcinoma (BRCA) cohort.Results: 4T1 exhibited a strikingly elevated surface expression of CD73 compared to other mouse cancer cell lines. Three CD73-derived peptides (EP1, EP2, EP3) consisting of 8-10 amino acids were synthesized. In vitro stimulation experiments indicated that EP1 and EP3 significantly elicited T-cell responses in draining lymph nodes. After stimulation, the proportions of CD25+, CD69+, CD107a+, and CD137+ cells markedly increased in CD8+ T cell populations. These cells also displayed enhanced cytotoxicity against 4T1 tumor cells. In vivo experiments demonstrated that EP3 induced a pronounced anti-tumor response in an established 4T1 tumor model without evident toxicity. Moreover, subcutaneous injection of EP3 improves the TME by promoting antigen-specific CD8+ T-cell responses, reducing M2 macrophages, and inducing neutrophil maturation. High tumor CD73 expression was also found to be associated with poor outcomes among BRCA patients, which further indicated clinical relevance. Conclusions: In this study, we successfully identified an immunogenic vaccine targeting CD73. It expressed dual functionality by effectively triggering cytotoxic T-cell responses that directly killing CD73-highexpressing tumor cells and regulating the tumor microenvironment through eliminating immunosuppressive cells with elevated CD73 expression. These findings hold promise for a novel immune-modulating vaccine and suggest a potential therapeutic avenue for the treatment of breast cancer and other types of cancer. Citation Format: Yuting Luo, Tao Shi, Hanbing Wang, Baorui Liu, Jia Wei. Immune-modulating vaccines targeting CD73 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4105.

Study on the structure–activity relationship of rice immunopeptides based on molecular docking

Research on food-derived immunoregulatory peptides has attracted increasing attention of scientists worldwide. However, the structure–activity relationship of rice immunopeptides was not clearly. Herein, 114 rice immunopeptides were obtained by simulating the enzymatic hydrolysis of rice proteins and were further analyzed by NetMHCIipan-4.0. Subsequently, the molecular docking was used to simulate the binding of immunoreactive peptides to major histocompatibility complex class II (MHC-II) molecules. Results show that S, R, D, E, and T amino acid could easily form hydrogen bonds with MHC-II molecules, thus enhancing innate and adaptive immunity. Finally, glucose-modified rice immunopeptides were to investigate the binding of the peptides with MHC-II molecules after glycosylation modification; this provided a theoretical basis for the targeted modification of the generated immunopeptides. All in all, the present study provides a theoretical foundation to further utilize rice processing byproducts and other food products to enhance immunity.

Visualising tapasin- and TAPBPR-assisted editing of major histocompatibility complex class-I immunopeptidomes.

Which peptides are selected for presentation by major histocompatibility complex class-I (MHC-I) molecules is a key determinant of successful immune responses. Peptide selection is co-ordinated by the tapasin and TAP Binding PRotein (TAPBPR) proteins, which ensure MHC-I molecules preferentially acquire high-affinity-binding peptides. New structural analyses have offered insight into how tapasin achieves this function within the peptide-loading complex (PLC) (comprising the Transporter associated with Antigen Presentation (TAP) peptide transporter, tapasin-ERp57, MHC-Iand calreticulin), and how TAPBPR performs a peptide editing function independently of other molecules. The new structures reveal nuances in how tapasin and TAPBPR interact with MHC-I, and how calreticulin and ERp57 complement tapasin to exploit the plasticity of MHC-I molecules to achieve peptide editing.

Get into the groove! The influence of TAPBPR on cargo selection

Since the discovery of Transporter associated with antigen processing-binding protein-related (TAPBPR) over two decades ago, extensive studies have explored its function in the context of the major histocompatibility complex class-I (MHC-I) antigen processing and presentation pathway. As a chaperone and peptide editor, TAPBPR was recently revealed to have overlapping structural features when resolved with peptide-receptive MHC-I molecules compared with the two newly solved tapasin:MHC-I structures. Despite this, the two chaperones seem to have a unique criteria for loading high-affinity peptides on MHC-I molecules. Yet, the mechanism of action of how TAPBPR creates its distinct filter in cargo selection for peptide-receptive MHC-I molecules continues to be a subject of debate.

Evolutionarily conserved amino acids in MHC-II mediate bat influenza A virus entry into human cells

The viral hemagglutinins of conventional influenza A viruses (IAVs) bind to sialylated glycans on host cell surfaces for attachment and subsequent infection. In contrast, hemagglutinins of bat-derived IAVs target major histocompatibility complex class II (MHC-II) for cell entry. MHC-II proteins from various vertebrate species can facilitate infection with the bat IAV H18N11. Yet, it has been difficult to biochemically determine the H18:MHC-II binding. Here, we followed a different approach and generated MHC-II chimeras from the human leukocyte antigen DR (HLA-DR), which supports H18-mediated entry, and the nonclassical MHC-II molecule HLA-DM, which does not. In this context, viral entry was supported only by a chimera containing the HLA-DR α1, α2, and β1 domains. Subsequent modeling of the H18:HLA-DR interaction identified the α2 domain as central for this interaction. Further mutational analyses revealed highly conserved amino acids within loop 4 (N149) and β-sheet 6 (V190) of the α2 domain as critical for virus entry. This suggests that conserved residues in the α1, α2, and β1 domains of MHC-II mediate H18-binding and virus propagation. The conservation of MHC-II amino acids, which are critical for H18N11 binding, may explain the broad species specificity of this virus.

MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange

Presentation of antigenic peptides by major histocompatibility complex class II (MHC-II) proteins determines T helper cell reactivity. The MHC-II genetic locus displays a large degree of allelic polymorphism influencing the peptide repertoire presented by the resulting MHC-II protein allotypes. During antigen processing, the human leukocyte antigen (HLA) molecule HLA-DM (DM) encounters these distinct allotypes and catalyzes exchange of the placeholder peptide CLIP by exploiting dynamic features of MHC-II. Here, we investigate 12 highly abundant CLIP-bound HLA-DRB1 allotypes and correlate dynamics to catalysis by DM. Despite large differences in thermodynamic stability, peptide exchange rates fall into a target range that maintains DM responsiveness. A DM-susceptible conformation is conserved in MHC-II molecules, and allosteric coupling between polymorphic sites affects dynamic states that influence DM catalysis. As exemplified for rheumatoid arthritis, we postulate that intrinsic dynamic features of peptide–MHC-II complexes contribute to the association of individual MHC-II allotypes with autoimmune disease.

SHP-1 localization to the activating immune synapse promotes NK cell tolerance in MHC class I deficiency.

Natural killer (NK) cells recognize virally infected cells and tumors. NK cell function depends on balanced signaling from activating receptors, recognizing products from tumors or viruses, and inhibitory receptors (such as KIR/Ly49), which recognize major histocompatibility complex class I (MHC-I) molecules. KIR/Ly49 signaling preserves tolerance to self but also conveys reactivity toward MHC-I-low target cells in a process known as NK cell education. Here, we found that NK cell tolerance and education were determined by the subcellular localization of the tyrosine phosphatase SHP-1. In mice lacking MHC-I molecules, uneducated, self-tolerant Ly49A+ NK cells showed accumulation of SHP-1 in the activating immune synapse, where it colocalized with F-actin and the signaling adaptor protein SLP-76. Education of Ly49A+ NK cells by the MHC-I molecule H2Dd led to reduced synaptic accumulation of SHP-1, accompanied by augmented signaling from activating receptors. Education was also linked to reduced transcription of Ptpn6, which encodes SHP-1. Moreover, synaptic SHP-1 accumulation was reduced in NK cells carrying the H2Dd-educated receptor Ly49G2 but not in those carrying the noneducating receptor Ly49I. Colocalization of Ly49A and SHP-1 outside of the synapse was more frequent in educated compared with uneducated NK cells, suggesting a role for Ly49A in preventing synaptic SHP-1 accumulation in NK cell education. Thus, distinct patterning of SHP-1 in the activating NK cell synapse may determine NK cell tolerance.

A Bimetallic Metal-Organic-Framework-Based Biomimetic Nanoplatform Enhances Anti-Leukemia Immunity via Synchronizing DNA Demethylation and RNA Hypermethylation.

Epigenetic-alterations-mediated antigenicity reducing in leukemic blasts (LBs) is one of the critical mechanisms of immune escape and resistance to T-cell-based immunotherapy. Herein, a bimetallic metal-organic framework (MOF)-based biomimetic nanoplatform (termed as AFMMB) that consists of a DNA hypomethylating agent, a leukemia stem cell (LSC) membrane, and pro-autophagic peptide is fabricated. These AFMMB particles selectively target not only LBs but also LSCs due to the homing effect and immune compatibility of the LSC membrane, and induce autophagy by binding to the Golgi-apparatus-associated protein. The autophagy-triggered dissolution of AFMMB releases active components, resulting in the restoration of the stimulator of interferon genes pathway by inhibiting DNA methylation, upregulation of major histocompatibility complex class-I molecules, and induction of RNA-methylation-mediated decay of programmed cell death protein ligand transcripts. These dual epigenetic changes eventually enhance T-cell-mediated immune response due to increased antigenicity of leukemic cells. AFMMB also can suppress growth and metastases of solid tumor, whichwassuggestive of a pan-cancer effect. These findings demonstrate that AFMMB may serve as a promising new nanoplatform for dual epigenetic therapy against cancer and warrants clinical validation.

Transcriptomic analysis reveals the immune response of human microglia to a soy protein and collagen hybrid bioscaffold

Inflammatory reactions resulting from spinal cord injury cause significant secondary damage. Microglial cells activate CD4+ T cells via major histocompatibility complex class II (MHCII) molecules. The activated T cells lead to neural tissue damage and demyelination at early stages of spinal cord injury. Control of the inflammatory response may attenuate the injury process. In this study, we compared gene expression in human microglia grown on soy protein-collagen hybrid scaffolds versus collagen scaffolds. Differentially expressed genes (DEGs) were subjected to gene ontology (GO) and pathway enrichment assays. Among down-regulated genes, the “antigen processing and presentation” pathway shows enrichment, primarily due to the down-regulation of MHCII molecules. The DEGs in this pathway show enrichment of binding sites for several transcription factors, with CIITA and IRF8 being the top candidates. The down-regulation of MHCII along with the significant enrichment of the GO term “focal adhesion” among the up-regulated genes helps explain the higher motility of microglial cells on the hybrid scaffold compared with that on the collagen scaffold. Up-regulated genes associated with “focal adhesion” include DNM2, AHNAK, and HYOU1, which have been previously implicated in increased cell motility. Overall, our study indicates that the use of hybrid scaffolds containing soy protein and collagen may modulate the immune response of wounded neural tissue.

Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules.

Major Histocompatibility Complex class I (MHC-I) molecules display self, viral or aberrant epitopic peptides to T cell receptors (TCRs), which employ interactions between complementarity-determining regions with both peptide and MHC-I heavy chain 'framework' residues to recognize specific Human Leucocyte Antigens (HLAs). The highly polymorphic nature of the HLA peptide-binding groove suggests a malleability of interactions within a common structural scaffold. Here, using structural data from peptide:MHC-I and pMHC:TCR structures, we first identify residues important for peptide and/or TCR binding. We then outline a fixed-backbone computational design approach for engineering synthetic molecules that combine peptide binding and TCR recognition surfaces from existing HLA allotypes. X-ray crystallography demonstrates that chimeric molecules bridging divergent HLA alleles can bind selected peptide antigens in a specified backbone conformation. Finally, in vitro tetramer staining and biophysical binding experiments using chimeric pMHC-I molecules presenting established antigens further demonstrate the requirement of TCR recognition on interactions with HLA framework residues, as opposed to interactions with peptide-centric Chimeric Antigen Receptors (CARs). Our results underscore a novel, structure-guided platform for developing synthetic HLA molecules with desired properties as screening probes for peptide-centric interactions with TCRs and other therapeutic modalities.

SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to down-regulate MHC-I surface expression

Major histocompatibility complex class I (MHC-I) molecules, which are dimers of a glycosylated polymorphic transmembrane heavy chain and the small-protein β2-microglobulin (β2m), bind peptides in the endoplasmic reticulum that are generated by the cytosolic turnover of cellular proteins. In virus-infected cells, these peptides may include those derived from viral proteins. Peptide-MHC-I complexes then traffic through the secretory pathway and are displayed at the cell surface where those containing viral peptides can be detected by CD8+ T lymphocytes that kill infected cells. Many viruses enhance their invivo survival by encoding genes that down-regulate MHC-I expression to avoid CD8+ T cell recognition. Here, we report that two accessory proteins encoded by SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic, down-regulate MHC-I expression using distinct mechanisms. First, ORF3a, a viroporin, reduces the global trafficking of proteins, including MHC-I, through the secretory pathway. The second, ORF7a, interacts specifically with the MHC-I heavy chain, acting as a molecular mimic of β2m to inhibit its association. This slows the exit of properly assembled MHC-I molecules from the endoplasmic reticulum. We demonstrate that ORF7a reduces antigen presentation by the human MHC-I allele HLA-A*02:01. Thus, both ORF3a and ORF7a act post-translationally in the secretory pathway to lower surface MHC-I expression, with ORF7a exhibiting a specific mechanism that allows immune evasion by SARS-CoV-2.

Association of HLA Class I Genotype with Mortality in Patients with Diabetes Mellitus and COVID-19

Numerous studies showed that diabetes mellitus (DM) increases the risk of death from COVID-19 by five times. It is generally accepted that the high lethality of COVID-19 against the background of DM is due to the main complications of this disease: micro- and macroangiopathies, as well as heart and kidney failure. In addition, it was shown that acute respiratory viral infection increases the production of interferon gamma, increases muscle resistance to insulin, and modulates the activity of effector CD8+ T cells. The ability of CD8+ T cells to recognize SARS-CoV-2-infected cells depends not only on humoral factors but also on individual genetic characteristics, including the individual set of major histocompatibility complex class I (MHC-I) molecules. In this study, the relationship of the MHC-I genotype of patients with DM aged less than 60 years with the outcome of COVID-19 was studied using a sample of 222 patients. It was shown that lethal outcomes of COVID-19 in patients with DM are associated with the low affinity of the interaction of an individual set of MHC-I molecules with SARS-CoV-2 peptides.

Nonlysosomal Route of mRNA Delivery and Combining with Epigenetic Regulation Optimized Antitumor Immunoprophylactic Efficacy.

Currently, mRNA-based tumor therapies are in full flow because in vitro-transcribed (IVT) mRNA has the potential to express tumor antigens to initiate the adaptive immune responses. However, the efficacy of such therapy relies heavily on the delivery system. Here, a pardaxin-modified liposome loaded with tumor antigen-encoding mRNA and adjuvant (2',3'-cGAMP, (cyclic [G(2',5')pA(3',5')p])), termed P-Lipoplex-CDN is reported. Due to an nonlysosomal delivery route, the transfection efficiency on dendritic cells (DCs) is improved by reducing the lysosome disruption of cargos. The mRNA modified DCs efficiently induce tumor antigen-specific immune responses both in vitro and in vivo. As prophylactic vaccines, mRNA transfected DCs significantly delay the occurrence and development of tumors, and several immunized mice are even completely resistant to tumors. Interestingly, the efficacy depends on the major histocompatibility complex class I (MHC-I) expression level on tumor cells. Furthermore, epigenetic modification (decitabine, DAC) is applied as a combination strategy to deal with malignant tumor progression caused by deficient tumor MHC-I expression. This study highlights the close relationship between mRNA-DCs vaccine efficacy and the expression level of tumor cell MHC-I molecules. Moreover, a feasible strategy for tumor MHC-I expression deficiency is proposed, which may provide clinical guidance for the design and application of mRNA-based tumor therapies.

Delayed Diagnosis of Chronic Necrotizing Granulomatous Skin Lesions due to TAP2 Deficiency.

Major histocompatibility complex class I (MHC-I) deficiency, also known as bare lymphocyte syndrome type 1 (BLS-1), is a rare autosomal recessively inherited immunodeficiency disorder with remarkable clinical and biological heterogeneity. Transporter associated with antigen processing (TAP) is a member of the ATP-binding cassette superfamily of transporters and consists of two subunits, TAP1 or TAP2. Any defect resulting from a mutation or deletion of these two subunits may adversely affect the peptide translocation in the endoplasmic reticulum, which is an important process for properly assembling MHC-I molecules. To date, only 12 TAP2-deficient patients were reported in the literature. Herein, we described two Iranian cases with 2 and 3 decades of delayed diagnosis of chronic necrotizing granulomatous skin lesions due to TAP2 deficiency without pulmonary involvement. Segregation analysis in family members identified 3 additional homozygous asymptomatic carriers. In both asymptomatic and symptomatic carriers, HLA-I expression was only 4-15% of the one observed in healthy controls. We performed the first deep immunophenotyping in TAP2-deficient patients. While total CD8 T cell counts were normal as previously reported, the patients showed strongly impaired naïve CD8 T cell counts. Mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cell counts were increased.