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Results for “B-Lymphocyte Subsets”

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PubMed2026

Transcriptome-Proteome Analysis of Human Naive and Memory B Cell Subsets Reveals Isotype and Subclass-Specific Phenotypes.

Antibodies produced by B cells aid in the recognition and clearance of pathogens and are the cornerstone of vaccination strategies. Humans produce nine different antibody isotypes, and their effector functions differ according to the type of antigen and route of exposure. Phenotypic variation between isotype-switched B cell subsets is expected but not studied in detail. To obtain a molecular definition of isotype-defined cell identity, we performed proteomics and transcriptomics on isotype-defined populations of human naive and memory B cells (MBCs): CD27-IgM+IgD+, CD27+CD38lo/-IgM+IgD+, CD27+CD38lo/-IgM+IgD-, and IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4 MBCs (CD27+CD38lo/-Ig+). Combined proteome and transcriptome analysis revealed that mRNA and protein expression profiles separate isotype-defined B cell subsets according to their differentiation status. mRNA and protein expression levels correlated reasonably well for many genes. IgG4-switched B cells were most distinct from naive B cells in terms of mRNA as well as protein expression profiles. Besides a distinct expression profile of cytokine and Fc receptors, we identified a high expression of IgE-coding mRNA in IgG4-switched B cells. SDR16C5 was identified as uniquely upregulated in IgG4-switched B cells. Taken together, this study highlights the distinct phenotypic profile of IgG4-switched B cells.

Humans↗

PubMed1977

Failure of T cells specific for strong histocompatibility antigens to cooperate with B cells for a humoral response.

Thymus-derived lymphocytes (T cells) selected for reactivity to strong histocompatibility antigens over a period of one to twelve months in vitro were tested for their ability to cooperate with bone marrow-derived lymphocytes (B cells) for a humoral response. If cultured with normal syngeneic or allogeneic spleen cells and sheep erythrocytes (SRBC) as immunogen, inhibition of the anti-SRBC response was observed. Similarly, in T cell-free spleen cells the alloreactive T cells did not stimulate a humoral response, indicating that they cannot exert cooperative activity on B cells. Since it was possible that the alloreactive T cells may cooperate with B cells in a humoral response to immunogens carrying histocompatibility antigens, hapten-coupled tumor cells were also used as immunogen. Though it is demonstrated that the alloreactive T cells do recognize the tumor cell immunogen, no stimulation of the B cells for a humoral response against the tumor cell is observed. This result, as well as the finding that the antigenic requirements for T helper cell priming and cell proliferation of the alloreactive T cells are different, suggests that these alloreactive T cells and helper T cells belong to different T cell subsets.

Animals↗

PubMed1975

Shared idiotypic determinants on B and T lymphocytes reactive against the same antigenic determinants. I. Demonstration of similar or identical idiotypes on IgG molecules and T-cell receptors with specificity for the same alloantigens.

Antigen-binding receptors on T lymphocytes and IgG antibodies with the same antigen-binding specificity as the T-cell receptors display shared or identical idiotypes. This was shown using a system where adult F1 hybrid rats between two inbred strains were inoculated with T lymphocytes from one parental strain. Such F1 hybrid rats produce antibodies directed against idiotypic determinants present on IgG alloantibodies, produced in the T donor genotype strain and with specificity for the alloantigens of the other parental strain. The idiotypic nature of the F1 antialloantibody serum against the parental alloantibodies was demonstrated both by indirect hemagglutination tests or by gel diffusion using alloantisera with different specificity as targets. Furthermore, the F1 anti-T-lymphocyte sera could be shown to contain antibodies against idiotypic parental T lymphocytes as well. This was shown by the capacity of the antisera, in the presence of complement, to wipe out the relevant parental T-cell reactivity against the other parental strain (as measured in MLC or GVH) whilst leaving the T-lymphocyte reactivity against a third, unrelated allogeneic strain intact. These findings demonstrate that F1 hybrid rats inoculated with parental T lymphocytes make anti-idiotypic antibodies directed against both the T cell receptors and IgG alloantibodies of that parental strain with specificity for alloantigens of the other parental strain. In order to prove identity between the anti-idiotypic antibodies against the B and T-cell antigen-binding molecules the following experiments were carried out; highly purified IgG from relevant alloantibody-containing serum in immunosorbent from could be shown to selectively remove both anti-idiotypic activities from the F1 antiserum. Further more, parental normal T lymphocytes could be shown capable of removing from the anti-idiotypic antisera all those antibodies that would cause agglutination of the relevant alloantibody-coated erythrocytes in the indirect agglutination assay. We would thus conclude that T and B lymphocytes reactive against a given antigenic determinant use receptors with antigen-binding areas coded for by the same variable gene subset(s).

Adsorption↗

PubMed1977

Carrier-directed anti-hapten responses by B-cell subsets.

The capacity of the trinitrophenyl (TNP) haptenic group, coupled to a series of chemically dissimilar carriers, to cross-stimulate putative T- dependent and T-independent murine B-cell subpepulations was determined by using an in vitro limiting dilution technique to generate primary IgM responses. It was found that TNP-Ficoll and TNP-dextran, two T- independent antigens with little or no polyclonal mitogenicity, stimulate the same population of anti-TNP precursors, which is distinct from the precursor population activated by TNP-bacterial lipopolysaccharide (LPS), a T-independent polyclonal mitogen, or TNP-horse erythrocytes (HRBC), a T-dependent antigen. On the other hand, TNP-LPS and TNP-HRBC activate the same precursor population, indicating that LPS can substitute for the T- cell signal in T-dependent B-cell responses, whereas nonmitogenic T- independent antigens cannot. However, the cumulative evidence from this and other laboratories strongly indicates that LPS and T-dependent antigens activate B cells by different mechanisms. Of particular interest, LPS is incapable of activating B cells responsive to weakly- or nonmitogenic T-independent antigens. Based on clonal burst size, T-dependent antigens are capable of inducing greater antigen-specific B-cell proliferation than T-independent antigens. However, TNP conjugates of Ficoll and dextran, which are relatively poor inducers of polyclonal B-cell activation, induced larger anti-TNP clones than did TNP-LPS, a strong polyclonal mitogen. The findings reinforce the evidence favoring existence of multiple B- cell subpopulations with distinctive activation pathways. They also strengthen the proposition that a given B-cell subset can be activated by more than one mechanism.

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PubMed1976

Immunological activities of rat lymphocytes. I. Mitogenic responses and surface markers of lymphocytes from normal, thymectomized and B rats.

Lymphocytes from the peripheral blood, thoracic duct, spleen and lymph nodes of normal, thymectomized (TX) and thymectomized lethally irradiated marrow reconstituted (TXBM or B rats) Lewis rats were studied for their ability to proliferate in vitro in the presence of Con A or PHA. At the same time the lymphoid tissues of these animals were examined for the presence of B cells or T cells by immunofluorescence staining with antiserums to rat immunoglobulins or rat brain antigens (ARBS), respectively. The specificity of ARBS fort T cells was first established in both cytotoxicity and immunofluoresecnce studies with thymocytes as well as pruified T and B cells. In various lymphoid tissues from TX and B rats, cells carrying brain antigens were found which were unable to respond to Con A and PHA. Thymectomy has a lesser effect on the response to Con A that to PHA; this was particularly true in the thoracic duct where, following thymectomy, lymphocytes continued to respond to Con A but lost their ability to respond to PHA. This suggests that the response to PHA and Con A may belong to different cells' subsets but that the ability to respond to either one of these mitogens may be impaired in cells carrying known T cell markers.

Animals↗

PubMed1979

Generation of anti-type III pneumococcal polysaccharide hybridomas from mice with an X-linked B-lymphocyte defect.

(CBA/N X BALB/c male)F1 mice bear on X-linked defect making them totally unresponsive to T-independent (TI), TI-2 antigens such as type III pneumococcal polysaccharide (SSS-III). We found that somatic cell hybrids between CB nonresponder spleen cells and NS1 plasmacytoma cells secreted antibody specific for SSS-III. The solid-phase binding of such antibody was completely inhibited by the addition of free antigen (SSS-III) and the amount of antibody detected in culture fluids ranged from 10 ng/ml to 10 micrograms/ml. Eight hybridoma clones were identified; all make antibody of the IgM class. These results indicate that the X-linked defect does not result in a deletion of a B-cell subset which responds to TI-2 antigens.

Animals↗

PubMedDate not supplied

Polyfunctional antibodies. Their biology and inheritance.

It seems likely that immunoglobulins have evolved from some archetypal molecule and those forms which are useful to the animal have been retained. It is this entire population of antibodies which forms the humoral immune system and in such a system, not only the properties of individual antibody combining regions, but the properties of the multiprotein system as a whole, are important for the defences of the body against pathogens. Antibody combining sites may bind a disparate set of structurally related and unrelated ligands. This multispecificity can be biologically meaningful: the same clone can be stimulated by different antigens. In this sense, cell surface immunoglobulins are multifunctional. The major biological consequence of antibody multispecificity is overlapping binding functions within subsets of the total antibody repertoire. The most significant impact of this overlap is: (1) it reduces the number of V genes necessary to code for the total number of combining sites; (2) the cross-stimulation of clones by structurally related and unrelated antigens may be instrumental in the normal maintenance of immune responsiveness and in addition, it may explain the ability to respond to unusual and less ubiquitous antigens; (3) the antigenic history of the animal may contribute to the maturation of the immune response by cross-stimulation of pre-selected clones of antigen binding cells.

Animals↗

PubMed1977

Ala-1: murine alloantigen of activated lymphocytes. II. T and B effector cells express ala-1.

Ala-1 (activated lymphocyte antigen-1) is a murine alloantigen expressed only on activated peripheral T and B lymphocytes. The presence or absence of Ala-1 on specific functional lymphocyte subsets was determined by treating the relevant cell population with anti-Ala-1 and complement, and assaying for residual functional activity. By this method, Ala-1 was shown to be on in vivo primed killer T cells cytotoxic for allogeneic tumor cells. It was also found on helper T cells generated in vivo to sheep red blood cells, and on IgM and IgG plaque-forming cells (PFC) to sheep red blood cells. In contrast, splenic precursors of helper cells and of IgM PFC to sheep red blood cells were completely resistant to treatment with anti-Ala-1 and complement. These findings indicate that effector cells can be distinguished from their nonactivated precursors by their expression of Ala-1.

Animals↗

PubMed2026

Integrated Genomic and Proteomic Analysis Reveals T-B Lymphocyte Signatures in the MYCN Driven "Immune Desert" of Specific Neuroblastoma Subtypes.

AIMS: This study aims to systematically dissect how MYCN amplification shapes the immunosuppressive tumor microenvironment (TME) in high-risk neuroblastoma, elucidating key mechanisms underlying immune evasion. METHODS: We performed an integrated multi-omics analysis of bulk RNA-seq (n = 721), single-cell RNA-seq (n = 9), proteomic data (n = 49) and spatial transcriptomics (Visium, with external validation in melanoma). Analyses included unsupervised clustering, cell-cell communication inference, transcriptional regulatory network reconstruction, and spatial proximity assessment to map the immune landscape. RESULTS: A distinct molecular subtype (Class C), defined by MYCN amplification and poor prognosis, exhibited a comprehensive "immune desert" phenotype characterized by low immune scores and minimal leukocyte infiltration. Single-cell analysis confirmed significant depletion of T and B lymphocytes within the Class C TME. Dysregulated transcriptional networks were identified, including upregulation of REL and EOMES in T cells-with EOMES potentially driving exhaustion via regulation of Transient Receptor Potential (TRP) genes, and REL inhibition enhancing cytotoxic function in vitro. A unique immunosuppressive B-cell subset (B7) engaged in enhanced crosstalk with exhausted T cells and harbored a MYC-centered network linked to cell cycle dysregulation and poor survival. Spatial transcriptomics revealed significant proximity between B7-active regions and Treg/exhaustion-enriched areas, externally validated in melanoma. Proteomic data validated elevated REL expression in MYCN-amplified tumors. CONCLUSION: This work delineates the immunosuppressive architecture of MYCN-driven neuroblastoma, revealing novel regulatory nodes within specific lymphocyte compartments. Integrating single-cell, spatial, and proteomic evidence, we propose REL inhibition as a therapeutic candidate, the EOMES/TRP axis as a bioinformatically supported hypothesis, and the B7/MYC hub as a hypothesis supported by transcriptomic and spatial evidence.

Humans↗

PubMed1978

Recognition of lysozyme by lymphocyte subsets.

Extensive studies with antisera from a variety of animals have failed to detect any cross-reactivity between egg white lysozyme and its reduced, S-carboxymethylated (CM-) derivative. In contrast, a number of studies addressing the specificity of T lymphocytes have revealed that these two forms of lysozyme cross-react rather extensively at that level. Preliminary attempts to eliminate this latter cross-reactivity by further denaturation and/or chemical modification have so far proven unsuccessful. In a second line of experimentation the response to CM-lysozyme of mice which are genetically unresponsive to native lysozyme was assessed and found deficient. The implications of these findings are discussed.

Animals↗

PubMed2026

Localized PD-1 CAR T therapy reprograms neuroinflammation.

B cell-depleting therapies are effective in multiple sclerosis (MS), yet some patients relapse, underscoring the need for more precise interventions. To identify new therapeutic targets, we generated a single-cell RNA sequencing (scRNA-seq) atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases. We found disease-associated enrichment of class-switched immunoglobulin G+ (IgG+) B cells and plasma cells in MS CSF. Unbiased analysis identified a rare disease-enriched subset of activated, T cell receptor (TCR)-restricted, PD-1+ T follicular helper-like cells with B cell-recruiting features. To target this population, we developed PD-1-directed chimeric antigen receptor (CAR) T cells that selectively depleted pathogenic PD-1+ CD4 T cells and locally released IL-10. This strategy attenuated central nervous system (CNS) inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models. These findings define a CNS-localized adaptive immune circuit in MS and nominate programmable PD-1 CAR T cells as a strategy to disrupt it.

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PubMed2025

Identification of marginal zone B cells in head and neck cancer with immunomodulatory characteristics.

INTRODUCTION: Recently we observed high numbers of marginal zone B cells (MZBs) within murine head and neck squamous cell carcinoma (HNSCC) with immunosuppressive potential. To date, MZBs have not been linked to tumor development or tumor prevention. OBJECTIVES: Based on our previous findings the present study aimed to validate the presence of MZB in HNSCC and to investigate their possible implications in tumorigenesis and prognosis. METHODS: Flow cytometry was used to uncover MZB within tumors and blood of HNSCC patients. A single-cell RNA sequencing cohort of 118 HNSCC patients across different disease stages and 6 healthy donors (HDs) was compiled. Comparative transcriptomic profiling of B lymphocytes between HNSCC and HDs were performed. Downstream analysis, such as pathway enrichment, cell-cell communication, pseudotime trajectory inference, survival correlation, and spatial transcriptomics were applied. RESULTS: Two MZB subsets were revealed in tissues and blood of HNSCC patients and HDs. The tumor-associated MZBs were featured with hypoxia stress and viral-related hallmark genes. MZB-2, characterized by elevated expression of activation markers and immune-regulatory genes, displayed strong interactions with CD4+ T cells and antigen-presenting cells. These interactions were supported by costimulatory signals in HDs but were absent in HNSCC patients. Co-localization of MZB-2, germinal center B cell (GCB), and CD4+ follicular helper T cell (Tfh) was detected in HNSCC, suggesting the presence of an intratumoral MZB-Tfh-GCB axis. Clinically, MZB-2 abundance was associated with favorable prognosis in early-stage HNSCC, but not in advanced disease. Immunosuppressive gene signatures were not exclusive to MZBs, indicating that they do not represent a purely regulatory B cell phenotype. CONCLUSION: Our findings demonstrate an immunomodulatory role of MZBs in tumor immunity, balancing antigen presentation, cytokine signaling, and immune suppression. The association of MZB-2 with improved prognosis in early-stage HNSCC highlights its potential as a beneficial regulator of antitumor immunity during early tumor progression.

Humans↗

PubMed2026

An immunoinformatics-based multi-epitope vaccine candidate confers cross-protection against two Actinobacillus pleuropneumoniae serovars.

Porcine contagious pleuropneumonia (PCP) is caused by Actinobacillus pleuropneumoniae (APP) and inflicts heavy economic losses on the swine industry. However, existing inactivated vaccines provide limited cross-protection, highlighting the need for improved vaccine strategies. In this study, we combined pangenome analysis with subtractive proteomics to screen the APP core genome and identified 11 potential antigens. Seven of them showed immunoreactivity by ELISA and Western blotting. These antigens, together with the ApxI-III toxins, were used for T and B cell epitope prediction. On this basis, a multi-epitope fusion protein MVAPP was constructed. In silico molecular docking with swine immune receptors and immune simulations suggested that MVAPP has the potential to induce immune responses. In the mouse model, that MVAPP elicited specific antibody responses, shifted the splenic T-cell subset distribution toward CD4+ T cells, and provided partial protection against challenge with strains from two serovars. In conclusion, MVAPP represents a potential multi-epitope vaccine candidate for further development against APP.

Animals↗

PubMed2026

TGF-β and IL-2 differentially shape T follicular regulatory cell differentiation and stability in vitro.

T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells play critical roles in regulating the activity of the germinal center (GC), which is essential for the generation of high-affinity antibodies. In the GC, Tfh cells help B cells to proliferate and to differentiate into memory B cells and long-lived plasma cells. In contrast, Tfr cells, a specialized subset of regulatory T cells (Tregs), modulate the humoral immune response by suppressing excessive or autoreactive B-cell activity. Here, we established an in vitro differentiation protocol for mouse CD4⁺ T cells that yielded CXCR5⁺FoxP3⁺ Tfr cells that exhibited a Bcl6hiPD-1hiCD25loGITRint phenotype and were distinct from Treg and Tfh cells. Functionally, in vitro-generated Tfr cells potently suppressed Tfh cell-driven B-cell class switching to IgG1 and downregulated the expression of B-cell costimulatory ligands. While in vitro-generated Bcl6-deficient Tfh cells were impaired in providing help to B cells for efficient class switching to IgG1, in vitro-generated Bcl6-deficient Tfr cells failed to inhibit Tfh cell-driven B-cell class switching to IgG1. Mechanistically, we showed that Tfr cells emerged from FoxP3+ precursors in low-IL-2 environments through a TGF-β- and c-Maf-dependent pathway, allowing for reprogramming and reinforcement of the follicular regulatory cell program in CD4+ T cells in vitro.

Animals↗

PubMed2025

Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age.

The immune system comprises multiple cell lineages and subsets maintained in tissues throughout the lifespan, with unknown effects of tissue and age on immune cell function. Here we comprehensively profiled RNA and surface protein expression of over 1.25 million immune cells from blood and lymphoid and mucosal tissues from 24 organ donors aged 20-75 years. We annotated major lineages (T cells, B cells, innate lymphoid cells and myeloid cells) and corresponding subsets using a multimodal classifier and probabilistic modeling for comparison across tissue sites and age. We identified dominant site-specific effects on immune cell composition and function across lineages; age-associated effects were manifested by site and lineage for macrophages in mucosal sites, B cells in lymphoid organs, and circulating T cells and natural killer cells across blood and tissues. Our results reveal tissue-specific signatures of immune homeostasis throughout the body, from which to define immune pathologies across the human lifespan.

Humans↗

PubMed1979

Antigenic marker on a functional subpopulation of B cells, controlled by the I-A subregion of the H-2 complex.

CBA/N mice have an X-linked recessive effect that results in the absence of a subpopulation of B cells carrying the Lyb3 surface marker. It has been shown previously that this marker is present on a mature subset of B cells in all mouse strains. In this paper the Lyb3+ B cell population in C57BL/6 mice was analyzed further. This subset of B cells selectively expresses a surface marker controlled by the I-A subregion of the H-2 complex. A cytotoxic antiserum recognizing this marker was raised by immunizing defective (CBA/N X C57BL/6)F1 male mice with C57BL/6 spleen cells. This antiserum also contained noncytotoxic, non-strain-restricted anti-Lyb3 antibodies. The possible functional relevance of this surface marker is discussed.

Animals↗

PubMed1978

Mechanisms of clonal abortion tolerogenesis. I. Response of immature hapten-specific B lymphocytes.

B lymphocytes with receptors specific for the hapten fluorescein (FLU) were prepared from the spleens of mice of various ages. For most experiments, a one-step fractionation procedure based on the adherence of FLU-specific cells to FLU-gelatin was used. For some experiments, a subset of higher FLU-binding capacity was prepared from the FLU-gelatin binding population through the use of the fluorescence-activated cell sorter (FACS). FLU-specific B cells were placed into microculture with either FLU(3.6)-human gamma globulin (FLU(3.6)HGG) or FLU(12)HGG usually for 24 h at 37 degrees C. The tolerogen was then removed and 0.1 mug/ml of a T-independent antigen, FLU-polymerized flagellin, was substituted. 3 days later, cells were harvested from the microcultures and assayed for FLU-specific plaque-forming cells to determine any reduction in clonable hapten-specific B cells which the tolerogenesis treatment might have induced. The results showed that with FLU(3.6)HGG, hapten-specific newborn B cells could be tolerized at 1,000-fold lower tolerogen concentrations than adult splenic B cells of equal antigen-binding capacity. The high-avidity subset was even more susceptible to tolerance induction. Tolerance could be induced within 8 but not within 2 h, and at lower tolerogen concentrations, longer periods of tolerogenesis were required for a given effect. Using a 24-h tolerogenesis phase, 50 percent reduction in clone frequency among newborn FLU-gelatin fractionated cells was achieved at 0.08 mug/ml of FLU(3.6)HGG. Tolerance induction in immature B cells was inhibited by the concomitant presence of a polyclonal B-cell activator, Escherichia coli lipopolysaccharide (LPS) but tolerance once induced, was stable to challenge with LPS. Tolerogenesis was hapten specific. The proportion of tolerizable cells in spleens decreased with increasing age, reaching 50 percent at around 9 days. FLUI(12)HGG proved a more powerful tolerogen than FLU(3.6)HGG. It had an effect on adult cells, 50 percent reduction in clone frequency being noted at around 1 mug/ml. However, and in contrast to results claimed for other T- independent systems, there still was a major difference between immature and mature B cells, the immature cells displaying much greater sensitivity to tolerogenesis.

Animals↗

PubMed1979

In vitro model for natural tolerance to self-antigens. Inhibition of the development of surface-immunoglobulin-negative lymphocytes into T-dependent responsive B cells by antigen.

Neonatal and adult splenic cell suspensions were labeled with fluorescein isothiocynate-anti-Ig and fractionated into surface-immunoglobulin- (s-Ig) positive and s-Ig-negative subpopulations by the fluorescence-activated cell sorter. The subpopulations were then tested by splenic focus assay for both frequency and tolerance susceptibility of clonable 2,4,-dinitrophenol (DNP) precursors. It was shown that both adult, and neonatal, s-Ig-negative subsets contained clonable DNP-specific B-cell precursors. However, because these precursors result in fewer clones secreting IgG, they appeared to be less mature than the s-Ig-positive precursors. In the absence of helper T cells, it was found that exposure of s-Ig-negative lymphocytes to tolerogen during the process in which they were acquiring surface receptors resulted in nearly total abrogation of potential DNP clones. This finding provides compelling evidence for clonal abortion.

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