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Mucosal viral infection elicits long-lived IgA responses via type 1 follicular helper T cells.

Although immunoglobulin A (IgA)+ long-lived plasma cells (LLPCs) generated following mucosal viral infection provide durable protection against reinfection, little is known about their generation. Here, we show that rotavirus (RV) infection induces gut-resident LLPCs that produce highly mutated, protective IgA. Unlike RV-specific immunoglobulin G (IgG)+ LLPCs, IgA+ LLPCs were generated independently of major histocompatibility complex class II (MHC class II) expression by dendritic cells-rather, MHC class II on B cells was both necessary and sufficient. B cell-MHC class II was also sufficient …

NO-Enhanced Sonodynamic Nanovesicles with Co-Stimulatory Molecule Self-Presentation for Multidimensional Tumor Immunotherapy.

Synergistically improving T cell responsiveness represents a promising therapeutic strategy for tumors; however, current treatments struggle … dritic cell (DC) membranes, from genetically engineered tumor cells, simultaneously present peptide-major histocompatibility complex class I (pMHC-I) and CD86, enabling homologous tumor targeting but also mimicking the antigen presentation and costimulatory signaling of DCs to directly activate infiltrating T lymphocytes. In multiple murine models, this nanovaccine demonstrated r …

Germline variants and mosaic chromosomal alterations affect COVID-19 vaccine immunogenicity.

Vaccine immunogenicity is influenced by the vaccinee's genetic background. Here, we perform a genome-wide association study of vaccine-induced SARS-CoV-2-specific immunoglobulin G (IgG) antibody titers and T cell immune responses in 1,559 mRNA-1273 and 537 BNT162b2 vaccinees of Japanese ancestry. SARS-CoV-2-specific antibody titers are associated with the immunoglobulin heavy chain (IGH) and major histocompatibility complex (MHC) locus, and T cell responses are associated with MHC. The lead variants at IGH contain a population-specific missense variant (rs1043109-C; p.Leu192Val) in the immunog…

EZH2 inhibition mitigates HIV immune evasion, reduces reservoir formation, and promotes skewing of CD8+ T cells toward less-exhausted phenotypes.

Persistent HIV reservoirs in CD4+ T cells pose a barrier to curing HIV infection. We identify overexpression of enhancer of zeste homolog 2 (EZH2) in HIV-infected CD4+ T cells that survive cytotoxic T lymphocyte (CTL) exposure, suggesting a mechanism of CTL resistance. Inhibition of EZH2 with the US Food and Drug Administration-approved drug tazemetostat increases surface expression of major histocompatibility complex (MHC) class I on CD4+ T cells, counterbalancing HIV Nef-mediated MHC class I downregulation. This improves CTL-mediated elimination of HIV-infected cells and suppresses viral rep…

Human gut M cells resemble dendritic cells and present gluten antigen.

Microfold (M) cells are rare intestinal epithelial cells that reside in the follicle-associated epithelium of Peyer's patches1. M cells tran … cilitating luminal antigen transport, human M cells also directly present antigens via the class II major histocompatibility complex (MHC-II). Notably, the related enterocytes only express MHC-II in chronic inflammatory states and do not express typical dendritic cell markers. Human M cells physiologically express a gene profile that resembles that of dendritic cells. Similar to …

Когнентная взаимозависимая патогенность клеток менингеальных В вызывает рецидив нейроинфламмации.

Клетки В являются главными движущими силами аутоиммунных расстройств центральной нервной системы (КНС), включая множественный склероз (МС). Хотя мозговые репертуары обычно содержат строго нереактивный репертуар клеток B, вопрос о том, как нарушение этой локальной иммунной терпимости способствует патологии, остается неясным. Здесь мы продемонстрировали, что автоматически реактивные клетки В на границе мозга ускоряют нейроинфламму, непосредственно используя энцефалитогенные клетки Т. Инъекции инъекции Intsoluerna magna, используемые для селективной манингеальных клеток B в модели 2D2 для передач

Совпадение в аннотации оригинала
B cells are central drivers of central nervous system (CNS) autoimmune disorders, including multiple sclerosis (MS). Although the brain meni … ing neutrophil recruitment and endothelial activation before disease onset. This mechanism required major histocompatibility complex class II (MHC class II) expression by B cells and granulocyte-macrophage colony-stimulating factor (GM-CSF) production by T cells. Furthermore, targeted depletion of brain-localized B cells attenuated EAE relapses in a passive EAE model. These findi …

An IL-2 mutein increases regulatory T cell suppression of dendritic cells via IL-10 and CTLA-4 to promote T cell anergy.

Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3+ regulatory T (TR) cells are in clinical trials for treating inflammatory diseases. Using an Fc-fused IL-2 mutein (Fc.IL-2 mutein) we developed that prevents diabetes in non-obese diabetic (NOD) mice, we show that Fc.IL-2 mutein induced an activated TR population with elevated proliferation, a transcriptional program associated with Stat5- and T cell receptor-dependent gene modules, and high IL-10 and CTLA-4 expression. Increased IL-10 signaling limited surface major histocompatibility complex class II u…

Epithelial recognition and elimination against aberrant cells.

Epithelial cells, which are non-immune cells, not only function as a physical defence barrier but also continuously monitor and eliminate aberrant epithelial cells in their vicinity. In other words, it has become evident that epithelial cells possess immune cell-like functions. In fact, recent research has revealed that epithelial cells recognise the Major Histocompatibility Complex I (MHC-I) of aberrant cells as a mechanism for surveillance. This cellular defence mechanism of epithelial cells probably detects aberrant cells more promptly than the conventional immune response, making it a nove…

PD-1 and CD73 on naive CD4+ T cells synergistically limit responses to self.

Vaccination with self- and foreign peptides induces weak and strong expansion of antigen-specific CD4+ T cells, respectively, but the mechanism is not known. In the present study, we used computational analysis of the entire mouse major histocompatibility complex class II peptidome to test how much of the naive CD4+ T cell repertoire specific for self-antigens was shaped by negative selection in the thymus and found that negative selection only partially explained the difference between responses to self and foreign. In naive uninfected and unimmunized mice, we identified higher expression of …

Inverse relationship between polygenic risk burden and age of onset of autoimmune vitiligo.

Vitiligo is a common autoimmune disease characterized by patches of depigmented skin and overlying hair due to destruction of melanocytes in … rlier age. Nevertheless, the correlation is not simple. In individuals who carry a single high-risk major histocompatibility complex class II haplotype, the effect of additional polygenic risk on vitiligo AOO is reduced. Particularly among those with early-AOO vitiligo (onset ≤12 years of age), genetic risk can reflect contributions from high common-variant burden but also rare v …

Pharmacological induction of MHC-I expression in tumor cells revitalizes T cell antitumor immunity.

Antigen presentation by major histocompatibility complex class I (MHC-I) is crucial for T cell-mediated killing, and aberrant surface MHC-I expression is tightly associated with immune evasion. To address MHC-I downregulation, we conducted a high-throughput flow cytometry screen, identifying bleomycin (BLM) as a potent inducer of cell surface MHC-I expression. BLM-induced MHC-I augmentation rendered tumor cells more susceptible to T cells in coculture assays and enhanced antitumor responses in an adoptive cellular transfer mouse model. Mechanistically, BLM remodeled the tumor immune microenvir…

HLA-G - evolvement from a trophoblast specific marker to a checkpoint molecule in cancer, a narrative review about the specific role in breast- and gynecological cancer.

Human leukocyte antigen G (HLA-G) is known as a non-classical molecule of the major histocompatibility complex class Ib and downregulates the mother's immune response against the fetus during pregnancy, thereby generating immune tolerance. Due to the latter effect, HLA-G is also referred to as an immune checkpoint molecule. Originally identified on extravillous trophoblasts, HLA-G is already known to induce immune tolerance at various stages of the immune response, for example through cell differentiation and proliferation, cytolysis and cytokine secretion. Because of these functions, HLA-G is…

Human cytomegalovirus UL18 prevents priming of MHC-E- and MHC-II-restricted CD8+ T cells.

Rhesus cytomegalovirus (RhCMV) vectors elicit major histocompatibility complex (MHC)-E-restricted CD8+ T cells that stringently control simian immunodeficiency virus (SIV) in rhesus macaques. These responses require deletion of eight RhCMV chemokine-like open reading frames (ORFs) that are conserved in human cytomegalovirus (HCMV). To determine whether HCMV encodes additional, nonconserved inhibitors of unconventional T cell priming, we inserted 41 HCMV-specific ORFs into a chemokine-deficient strain (68-1 RhCMV). Monitoring of epitope recognition revealed that HCMV UL18 prevented unconvention…

Single-cell multiomic analysis of thymocyte development reveals drivers of CD4+ T cell and CD8+ T cell lineage commitment.

The development of CD4+ T cells and CD8+ T cells in the thymus is critical to adaptive immunity and is widely studied as a model of lineage commitment. Recognition of self-peptide major histocompatibility complex (MHC) class I or II by the T cell antigen receptor (TCR) determines the CD8+ or CD4+ T cell lineage choice, respectively, but how distinct TCR signals drive transcriptional programs of lineage commitment remains largely unknown. Here we applied CITE-seq to measure RNA and surface proteins in thymocytes from wild-type and T cell lineage-restricted mice to generate a comprehensive timel…

Single-cell analysis reveals the transcriptional alterations in the submandibular glands of aged mice.

OBJECTIVES: Aging-related salivary gland changes, such as lymphocyte infiltration and acinar cell loss decrease saliva secretion, thereby af … t SMGs. CONCLUSIONS: Gene Ontology analysis revealed increased expression levels of genes encoding major histocompatibility complex (MHC) class I components in the ductal component cells of aged SMGs. MHC class I expression may thus be associated with salivary gland aging.

Crystal structures of glycoprotein D of equine alphaherpesviruses reveal potential binding sites to the entry receptor MHC-I.

Cell entry of most alphaherpesviruses is mediated by the binding of glycoprotein D (gD) to different cell surface receptors. Equine herpesvirus type 1 (EHV-1) and EHV-4 gDs interact with equine major histocompatibility complex I (MHC-I) to initiate entry into equine cells. We have characterized the gD-MHC-I interaction by solving the crystal structures of EHV-1 and EHV-4 gDs (gD1, gD4), performing protein-protein docking simulations, surface plasmon resonance (SPR) analysis, and biological assays. The structures of gD1 and gD4 revealed the existence of a common V-set immunoglobulin-like (IgV-l…

Inhibition of IRAK1 Is an Effective Therapy for Autoimmune Hypophysitis in Mice.

Autoimmune hypophysitis (AH) is an autoimmune disease of the pituitary for which the pathogenesis is incompletely known. AH is often treated … n T cell differentiation or recruitment to the pituitary. Finally, rosoxacin downregulated class II major histocompatibility complex expression on antigen-presenting cells that may lead to impaired activation of autoantigen-specific T cells. These data suggest that IRAK1 may play a pathogenic role in AH and that rosoxacin may be an effective drug for AH and other inflammatory dis …

Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology.

X-box binding protein 1 (XBP1) is a member of the CREB/ATF basic region leucine zipper family transcribed as the unspliced isoform (XBP1-u), which, upon exposure to endoplasmic reticulum stress, is spliced into its spliced isoform (XBP1-s). XBP1-s interacts with the cAMP response element of major histocompatibility complex class II gene and plays critical role in unfolded protein response (UPR) by regulating the transcriptional activity of genes involved in UPR. XBP1-s is also involved in other physiological pathways, including lipid metabolism, insulin metabolism, and differentiation of immun…

Epithelial-myeloid exchange of MHC class II constrains immunity and microbiota composition.

Intestinal epithelial cells (IECs) have long been understood to express high levels of major histocompatibility complex class II (MHC class II) molecules but are not considered canonical antigen-presenting cells, and the impact of IEC-MHC class II signaling on gut homeostasis remains enigmatic. As IECs serve as the primary barrier between underlying host immune cells, we reasoned that IEC-intrinsic antigen presentation may play a role in responses toward the microbiota. Mice with an IEC-intrinsic deletion of MHC class II (IECΔMHC class II) are healthy but have fewer microbial-bound IgA, regula…

Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease ri