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At least 37 records · Page 2Linked to original sources
PubMed2024

Enhanced mucosal SARS-CoV-2 immunity after heterologous intramuscular mRNA prime/intranasal protein boost vaccination with a combination adjuvant.

Current COVID-19 mRNA vaccines delivered intramuscularly (IM) induce effective systemic immunity, but with suboptimal immunity at mucosal sites, limiting their ability to impart sterilizing immunity. There is strong interest in rerouting immune responses induced in the periphery by parenteral vaccination to the portal entry site of respiratory viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), by mucosal vaccination. We previously demonstrated the combination adjuvant, NE/IVT, consisting of a nanoemulsion (NE) and an RNA-based RIG-I agonist (IVT) induces potent systemic and mucosal immune responses in protein-based SARS-CoV-2 vaccines administered intranasally (IN). Herein, we demonstrate priming IM with mRNA followed by heterologous IN boosting with NE/IVT adjuvanted recombinant antigen induces strong mucosal and systemic antibody responses and enhances antigen-specific T cell responses in mucosa-draining lymph nodes compared to IM/IM and IN/IN prime/boost regimens. While all regimens induced cross-neutralizing antibodies against divergent variants and sterilizing immunity in the lungs of challenged mice, mucosal vaccination, either as homologous prime/boost or heterologous IN boost after IM mRNA prime, was required to impart sterilizing immunity in the upper respiratory tract. Our data demonstrate the benefit of hybrid regimens whereby strong immune responses primed via IM vaccination are rerouted by IN vaccination to mucosal sites to provide optimal protection against SARS-CoV-2.

Animals↗
PubMed2026

TCRspec: A Recognition Interface-Informed Multimodal Method for TCR-pMHC Specificity Prediction.

Specific recognition between T-cell receptors (TCRs) and peptide-major histocompatibility complexes (pMHCs) is central to adaptive immunity, yet accurate prediction of TCR-pMHC specificity remains challenging. Existing models mainly rely on sequence features or isolated molecular structures, limiting their ability to capture interface-level determinants within the ternary recognition complex. Here, we constructed the multimodal TCR-pMHC ternary complex (MM-TCR) data set, integrating paired TCR-pMHC sequences, V/J gene annotations, and modeled TCR-pMHC complex structures refined by short molecular dynamics-based relaxation. Based on MM-TCR, we developed TCRspec, an interpretable multimodal framework combining sequence embeddings, gene-usage features, and complex-level structural representations. Under a stringent CD-HIT TCR-cluster-disjoint split, TCRspec achieved an average AUROC of 0.896 and AUPRC of 0.882 across seven antigen-specific test data sets, outperforming representative baseline models. Cross-validation and ablation analyses confirmed the contribution of ternary complex structural information and MD-refined structures. In independent OOD peptide-TCR systems, TCRspec retained discriminative performance and identified model-inferred peptide positions associated with TCR recognition, providing a structure-informed framework for TCR specificity prediction.

Receptors, Antigen, T-Cell↗
PubMed2026

A single-cell atlas of multiple myeloma defines malignant archetypes and proliferative states.

Multiple myeloma (MM) is a plasma-cell malignancy with extensive genomic and transcriptional heterogeneity, limiting disease classification and precision therapy. Here we generated a clinically annotated, population-scale, single-cell atlas of MM from 341 individuals spanning the disease and treatment continuum. We identified five recurrent malignant transcriptional archetypes and an orthogonal proliferative program associated with genomic features, therapeutic resistance and clinical outcomes. Validation in the independent CoMMpass cohort demonstrated robustness, prognostic relevance and portability across platforms. We developed a single-cell, target-discovery pipeline prioritizing malignant enrichment, cell-type specificity and tissue restriction, identifying FCRL2 as a plasma-restricted or B cell-lineage-restricted surface target expressed by malignant plasma cells. FCRL2-targeted chimeric antigen receptor T cells demonstrated antigen-specific activity in vitro and survival benefit in vivo. Together, these data provide a clinically actionable blueprint for patient stratification and precision target nomination in plasma-cell malignancies.

Multiple Myeloma↗
PubMed2026

Airway microbiome diversity, intramucosal bacteria, and spatial immunity in asthmatic adults and controls.

RATIONALE: Asthma is characterized by disruption of the thoracic airway mucosae and loss of microbial diversity. Spatial profiling of the mucosal transcriptome may systematically discover mechanisms for microbial influences on immunity. OBJECTIVES: We investigated relationships between clinical measures, microbial communities, and the host mucosal transcriptome within different strata of bronchial biopsies in subjects with and without asthma. METHODS: We performed bronchoscopy in 65 asthmatic adults and 44 healthy controls, quantifying bacterial operational taxonomic units (OTUs) in bronchial brushings by 16S ribosomal RNA (rRNA) gene amplicon sequences. Biopsy histologic features were scored blind to diagnosis. Following 16S rRNA in situ hybridization of 44 biopsies, bacterial foci were scored in epithelium, basement membrane, and stroma. Global human gene expression was quantified in epithelial and stromal compartments using digital spatial profiling. MEASUREMENTS AND MAIN RESULTS: Clinical asthma was independently predicted by basement membrane abnormalities (BaseMA), endobronchial bacterial diversity, and circulating eosinophil counts, but not by specific OTU abundances. 16S rRNA staining revealed bacteria within epithelium and mucosa of all biopsies. Intramucosal bacteria counts correlated negatively with spatially organized coexpression networks encoding antigen-specific immunity, neutrophil functions, and matrix activation, whereas BaseMA correlated positively with the adaptive immunity module. Eosinophil counts correlated with epithelial bacterial counts and senescence pathways. Clinical asthma was accompanied by upregulation of a regulatory T-cell network. CONCLUSIONS: Asthma and its related phenotypes are accompanied by complex mucosal events that extend beyond eosinophilic pathways. Components of diverse airway microbiota may modify immunity by beneficial interactions within the mucosa.

Humans↗
PubMed2025

TRAIT: A Comprehensive Database for T-cell Receptor-antigen Interactions.

Comprehensive and integrated resources on interactions between T-cell receptors (TCRs) and antigens are still lacking for adoptive T-cell-based immunotherapies, highlighting a significant gap that must be addressed to fully understand the mechanisms of antigen recognition by T cells. In this study, we present the T-cell receptor-antigen interaction database (TRAIT), a comprehensive database that profiles the interactions between TCRs and antigens. TRAIT stands out due to its comprehensive description of TCR-antigen interactions by integrating sequences, structures, and affinities. It provides millions of experimentally validated TCR-antigen pairs, resulting in an exhaustive landscape of antigen-specific TCRs. Notably, TRAIT emphasizes single-cell omics as a major reliable data source for TCR-antigen interactions and includes millions of reliable non-interactive TCRs. Additionally, it thoroughly demonstrates the interactions between mutations of TCRs and antigens, thereby benefiting affinity optimization of engineered TCRs as well as vaccine design. TCRs on clinical trials are innovatively provided. With the significant efforts made toward elucidating the complex interactions between TCRs and antigens, TRAIT is expected to ultimately contribute superior algorithms and substantial advancements in the field of T-cell-based immunotherapies. TRAIT is freely accessible at https://pgx.zju.edu.cn/traitdb.

Receptors, Antigen, T-Cell↗
PubMed1975

Biological significance of Fc receptor-bearing cells among activated T lymphocytes.

Lethally irradiated mice injected with syngeneic thymocytes and immunized with protein antigens develop specific helper T cells. If injected with semiallogeneic thymocytes, such mice generate H-2 antigen-specific cytotoxic T cells. Most spleen cells from these chimeric mice possess Fc receptors. The present results demonstrate that the development of Fc-receptor-bearing cells in thymocyte-injected irradiation chimeras seemingly is due to the physiological conditions in the mice rather than to the specific immunization. As a corollary, both helper T cells and cytotoxic T cells did not have Fc receptors, at least not in their effector state. Thus, Fc receptors on T cells would seem irrelevant to their immune function.

Animals↗
PubMed2004

Ex vivo phenotype and frequency of influenza virus-specific CD4 memory T cells.

Recent advances in class II tetramer staining technology have allowed reliable direct ex vivo visualization of antigen-specific CD4 T cells. In order to define the frequency and phenotype of a prototype response to a nonpersistent pathogen, we have used such techniques to analyze influenza virus-specific memory CD4 T cells directly from blood. These responses are stably detectable ex vivo at low frequencies (range, 0.00012 to 0.0061% of CD4 T cells) and display a distinct "central memory" CD62L(+) phenotype.

CD4-Positive T-Lymphocytes↗
PubMed1978

Experimental models for prevention of graft-versus-host reaction in bone marrow transfution. III. Reversible and irreversible differentiation of lymphocytes destined for cytotoxicity to effector cells for splenomegaly.

When lymphoid cells were obtained from AKR donors 12 h after a treatment with C57BL/L cells in complete Freund's adjuvant and transferred to (AKR X C57BL/6) F1 mice, splenomegaly in F1 recipients was augmented but cytotoxicity was suppressed. The suppression of cytotoxicity was antigen-specific. When cell transfer was carried out at stages as early as 3 or 6 h after the treatment of donors, cytotoxicity was enhanced but splenomegaly was suppressed. Irreversible deviation of immune response from the generation of cytotoxicity to the development of splenomegaly appears to occur within 12 h after such a treatment of donors.

Bone Marrow Transplantation↗
PubMed2026

Tracking GAD-specific T-cell expansions in Type 1 diabetes by intradermal GAD-Alum challenge.

Identifying and monitoring autoreactive T cells that drive beta cell destruction remains a major obstacle to developing effective immunotherapies for type 1 diabetes (T1D). These cells are extremely rare in peripheral blood and cannot be accessed directly from the pancreas. We used intradermal injection of Glutamic Acid Decarboxylase (GAD)-Alum to recruit GAD-specific T cells to accessible sites in the skin and skin-draining lymph nodes (LNs), sampled by skin suction blisters and ultrasound-guided LN aspiration. Peripheral blood samples obtained before GAD injection were restimulated with GAD in vitro to detect reactive CD4+ T cells. Single-cell RNA sequencing (scRNAseq) followed by re-expression of selected T cell receptors (TCRs) confirmed antigen specificity. Up to 70% of T cells at the skin injection site were clonally-expanded and 4 of 14 (28%) re-expressed TCRs were GAD-reactive. In LNs 1 of 14 (4%) clonally-expanded TCRs was GAD-reactive, representing ~0.08% of all T-cells. GAD-reactive cells across compartments displayed Th1 and Th17-associated transcription signatures. These results demonstrate the intradermal autoantigen challenge and scRNAseq, enable direct identification and molecular profiling of autoreactive T cells in vivo. This minimally invasive approach provides a powerful platform for tracking antigen-specific T cells to monitor disease activity and evaluate immune interventions in T1D.

Autoimmunity↗
PubMed2026

A Multiepitope Intranasal Adenoviral Vaccine Induces Robust Mucosal Immunity and Protection against SARS‑CoV‑2.

BACKGROUND: Vaccination has been central to mitigating the COVID-19 pandemic; however, the continual emergence of SARS-CoV-2 variants of concern (VOCs) has reduced the effectiveness of current intramuscular vaccines that primarily target the Spike (S) protein. Although updated formulations are periodically introduced, there remains a critical need for next-generation vaccine platforms capable of inducing broad, variant-independent protection. Here we evaluate a heterologous intranasal (i.n.) prime-boost vaccination strategy using bovine adenoviral (BAd) and chimpanzee adenoviral (ChAd) vectors expressing the S1 subunit in combination with either full-length membrane (M) and nucleocapsid (N) proteins (Ad-S1 + N + M) or multiepitope constructs derived from M and N (Ad-S1 + Epi/N + Epi/M). The constructs were incorporated with the autophagy-inducing peptide C5 (AIP-C5) to enhance antigen-specific T-cell responses. RESULTS: In BALB/c mice, Ad-S1 + Epi/N + Epi/M vaccination induced robust S1-specific immunity while simultaneously inducing strong N- and M-specific humoral and cellular responses that were comparable to or greater than those induced by Ad-S1 + N + M. All S1-containing formulations generated high neutralizing antibody titers (~ 3.8 log₁₀) against Omicron B.1.1.529 and BA.2.86 variants, although titers against the ancestral Wuhan strain were approximately one log₁₀ lower. In K18-hACE2 mice, i.n. immunization with S1-expressing vectors provided near-complete protection against BA.2.86 challenge, with undetectable lung viral titers and viral genome copies. CONCLUSION: An i.n. multiepitope adenoviral vaccine incorporating conserved SARS-CoV-2 antigens induces robust mucosal, humoral, and cellular immune responses and confers significant protection following SARS-CoV-2 challenge.

Animals↗
PubMed2025

SARS-CoV-2 infection and vaccination elicit distinct pharyngeal mucosal B cell responses in children.

Mucosal immunity is an important correlate of protection against respiratory infections such as SARS-CoV-2. Comparing B cell responses in the upper respiratory tract following vaccination and infection may offer unique insights into mucosal immunity. Here, we characterized antigen-specific B cells in the tonsils, adenoids, and peripheral blood of children who had been infected with SARS-CoV-2 or vaccinated with SARS-CoV-2 mRNA vaccines. SARS-CoV-2-specific switched memory B cells (BSM) and germinal center B cells were found in the blood and pharyngeal lymphoid tissues after vaccination or infection. However, infection generated a higher proportion of IgA+ BSM and CXCR3+CD21+ BSM, which showed distinct spatial localization, greater clonal expansion and increased propensity for plasma cell differentiation compared to their CXCR3- counterparts, accompanied by persistent activation of innate and T follicular helper cells in the tissues. Our data provide evidence for tissue-specific B cell memory after either SARS-CoV-2 vaccination or infection, but with distinct characteristics that can influence the quality, durability, and localization of immunity.

Journal Article↗
PubMed1978

The influence of salicyl-azo-sulfapyridine on the immune response to antigenic tumour cells inoculated into the coecal lumen of C3H mice.

Pretreatment of C3H mice with salicyl-azo-sulfapyridine (SASP) was found to increase the susceptibility of the intestine to malignant ascites cells inoculated into the coecal lumen. The response to intestinal immunization was radically changed by prior treatment of mice with SASP. In non-treated animals protection against a subsequent graft followed the intracoecal inoculation of ascites tumour cells. By prior treatment of the mice with SASP the protective immune response was suppressed and some of the treated animals showed enhanced tumour growth of the challenging graft. The immunological enhancement induced in SASP-treated animals was transferable by spleen cells to untreated mice. In sera from SASP-treated and intestinally immunized animals were found factors which in a competitive manner interfered with the binding of antibodies to antigenic sites on the tumour cell membrane. It is proposed that treatment with SASP modifies the intestinal immunity by suppressing antibody production and increasing production of antigen-specific factors lacking some of the immunoglobulin determinants.

Animals↗
PubMed1978

Interaction of cholera toxin and toxin derivatives with lymphocytes. III. Modulating effects in vivo by cholera toxin on the graft-versus-host reactivity of lymphoid cells: suggested inhibition of suppressor cells.

The influence of cholera toxin (CT), and thus probably of cyclic AMP, on the capacity of parental lymphoid cells to elicit a graft-versus-host reaction (GVHR) was studied. Toxin-treated DBA/1 mice were used as cell donors and untreated DBA/1xC57B1/6 F1 hybrid mice as recipients, and the GVHR reactivity of the transferred cells was estimated by their ability to induce spleen enlargement or stimulation of antibody formation ('allogenic effect') in the recipients. Spleen cells from donors intravenously injected with 1 microgram CT 1-3 days earlier, gave a significantly stronger GVHR than did spleen cells of untreated mice. Choleragenoid, a toxin analog devoid of the toxin's ability to activate plasma membrane adenylate cyclase even though it binds efficiently to cells, had no effect on the GVHR-inducing capacity of the spleen cells. The enhanced GVHR by spleen cells from toxin-treated DBA/1 animals was reduced to the normal level when the donor cells were transferred along with lymphoid cells from untreated animals of the same strain. Spleen was the most powerful source of the suppressive influence. No evidence for a redistribution of suppressor cells following administration of CT was found. Spleen cells from mice syngeneic with the recipients had no suppressive effect. The results suggest that parenterally administered CT, directly or indirectly, can inhibit a cell population in spleen which normally exerts an antigen-specific suppressive regulatory influence on the development of GVHR.

Cholera Toxin↗
PubMed1979

Differential depletion of T lymphocytes in the spleen of dengue virus-infected mice.

Following the i.c. inoculation of dengue type 2 virus (DV) the spleen weight of infected mice was reduced, as was the proportion of cells killed by ATS and complement (T lymphocytes) in spleen-cell suspensions. In DV-infected mice the mean haemolysin titre, 16 days after i.p. inoculation of 4 x 10(8) SRBC, was 47 compared with 406 in normal mice and spleen cells from DV-infected mice produced significantly reduced direct GVH reactivity in Parker strain (PS) infant mice. Adoptive transfer of spleen cells obtained from mice given three weeks i.p. doses of DV or a single i.c. dose, suppressed antigen-specific antibody secretion as detected by Jerne plaque technique. This suppression was abrogated by pretreating the transferred cells with ATS and complement. Thus DV selectively depletes T-lymphocyte subpopulations responsible for helper and effector functions and spares suppressor T cells in the spleen of infected mice.

Animals↗
PubMed1975

Anti-receptor antibody. I. Isolation and characterization of the immunoglobulin receptor for phosphorylcholine.

We have demonstrated a phosphorylcholine-binding protein in lysates from radioiodinated splenocytes of immunized mice. Immunoprecipitation with anti-receptor antibody of lysates from splenocytes obtained from animals undergoing a primary response or from mice immunized 4 to 6 months earlier with antigen demonstrated that this protein contained H and L chains. Therefore, we have isolated an antigen-specific receptor from the surface of spleen cells from both immunized and "memory" animals. This receptor Ig comprises approximately 10% of total cell surface Ig.

Animals↗
PubMed1975

Allotypic suppression in rabbits: competition for target cell receptors between isologous and heterologous antibody and between native antibody and antibody fragments.

Neonatal injection with various foreign proteins (normal goat serum, human Cohn fraction II, human albumin) caused a stimulation of immunoglobulin synthesis. This effect was not antigen-specific and did not constitute a conventional antibody response directed against the injected substance. When this stimulatory effect of foreign protein was minimized, the heterologous (goat) anti-rabbit allotype antibody and rabbit antibody F(ab') 2 fragments not only failed to induce suppression but also competed with the suppression-inducing native rabbit antibody. Allotypic suppression in a rabbit can thus only be induced by an antibody molecule possessing an intact Fc portion of isologous, rabbit origin. Antibody to Ae14, an allotypic specificity located on the Fc portion, failed to induce suppression or stimulation of immunoglobulin synthesis. This was attributed to the position of Ae14 in the cell membrane which reduced its accessibility to antibody.

Albumins↗
PubMed1975

Evidence for the clonal abortion theory of B-lymphocyte tolerance.

This paper deals with the behavior of adult mouse bone marrow cells placed in tissue culture with or without antigen, and subsequently assessed for immune competence after adoptive transfer into lethally X-irradiated, syngeneic hosts. Attention was focussed on B lymphocytes through using hapten human gamma globulin (HGG) preparations as putative tolerogens in tissue culture, the T-cell-independent antigens DNP-POL and NIP-POL as challenge injections in adoptive hosts, and numbers of hapten-specific PFC in host spleens for the quantitation of immune competence. It was found that the capacity of bone marrow cells to mount an adoptive immune response rose by a factor of about fivefold over 3 days in tissue culture. This rise was completely abolished by the presence in the culture of hapten-HGG conjugates with about one mole of hapten per carrier molecule. The prevention of the emergence of immune competence amongst maturing B cells was termed clonal abortion tolerogenesis. Dose-response studies showed the lowest effective antigen concentration to be between 2.5 times 10- minus 10 and 2.5 times 10- minus 9 M, and a standard concentration of 2.5 times 10- minus 8 M was chosen as producing near maximal effects. The tolerance was antigen-specific and time-dependent, being maximal only when antigen was present continuously as the cultured cells was maturing. It did not depend on the presence of T lymphocytes in marrow, and was not of an "infectious" type. In contrast to tolerogenesis of mature B lymphocytes by high antigen concentrations, it could not be abolished by lipopolysaccharide. We speculate that clonal abortion may be a tolerance mechanism of great physiological significance for self-recognition, and discuss the results in the framework of other recent tolerance models, including those involving receptor blockade and suppressor T cells.

Animals↗
PubMed1975

Early steps in specific tumor cell lysis by sensitized mouse T lymphocytes. I. Resolution and characterization.

Addition of high molecular weight dextran to culture medium prevents the initiation of T lymphocyte-mediated killing by holding the cytolytic T lymphocytes (CTL) and target cells in suspension and preventing intercellular contact. Suspension in 10% dextran was used to interrupt the ongoing formation of adhesions between CTL and target cells already in contact in a centrifuged pellet. The results demonstrate that 1) firm adhesions form between CTL and target cells within 1 min at 37 degrees C; 2) once formed, these adhesions are stable at low temperature and are resistant to mechanical shearing forces; 3) these adhesions can be disrupted by EDTA; 4) immediately after the adhesions form, separation of the CTL from the target cells prevents lysis of the latter; 5) after incubation of targets adhering to CTL for an additional 6 min at 37 degrees C, removal of the CTL no longer prevents target cell lysis. Thus, target cells become "programmed" for subsequent lysis within a few minutes after contact with CTL, after which lysis occurs during the next several hours without further participation of the effector cell. At 15 degrees C, adhesions form 1/17 as fast as at 37 degrees C. Programming of target cells for lysis occurs 1/76 as fast at 15 degrees C as at 37 degrees C. Thus, the programming for lysis step is about 4-fold more temperature dependent than the adhesion step. In addition to being detected by subsequent target cell lysis in 10% dextran, the adhering cell clusters can be counted with low power microscopy. This permitted verification that EDTA separates the clusters after programming for lysis is complete. Moreover, the great majority of the clusters seen at 37 degrees C are antigen-specific. Knowledge of the cluster size distribution and the subsequent level of lysis permits the deduction that not less than 6% of the sensitized peritoneal cell populations used were CTL.

Animals↗