Cognate Help Research Articles

Pre-existing CD4 T cell help boosts antibody responses but has limited impact on germinal center, antigen-specific B cell frequencies after influenza infection.

The influenza virus is a persistent burden on global health, with seasonal vaccines providing incomplete protection. CD4+ T cells help shape B cell and antibody responses; however, the selectivity of help and the effect on various antigen-specific B cell populations have not been fully elucidated. Here, we studied the specificity, selectivity, and influence of nucleoprotein (NP) CD4+ T cells on the magnitude and quality of hemagglutinin (HA) and NP-specific B cells and antibody responses. We identified immunodominant peptides and showed that peptide immunization was sufficient to induce CD4+ cells with Th1 and Tfh phenotypes. Surprisingly, while preexisting CD4+ T cells enhanced the influx of total germinal center (GC) B cells in the mediastinal lymph node after infection, this was not reflected by an increase in the frequency of antigen-specific cells within the GC. Furthermore, we demonstrated that NP-specific help was able to accelerate the kinetics and magnitude of the Ab response for NP but not for HA. Overall, our results showed that pre-existing CD4+ T cells provide strong cognate help during immunization or infection to enhance Ab production but not antigen-specific GC or memory B cells.

Nanocell COVID-19 vaccine triggers a novel immune response pathway producing high-affinity antibodies which neutralize all variants of concern.

Most current anti-viral vaccines elicit a humoral and cellular immune response via the pathway of phagocytic cell mediated viral antigen presentation to B and T cell surface receptors. However, this pathway results in reduced ability to neutralize S-protein Receptor Binding Domains (RBDs) from several Variants of Concern (VOC) and the rapid waning of memory B cell response requiring vaccine reformulation to cover dominant VOC S-proteins and multiple boosters. Here we show for the first time in mice and humans, that a bacterially derived, non-living, nanocell (EDV; EnGeneIC Dream Vector) packaged with plasmid expressed SARS-CoV-2 S-protein and α-galactosyl ceramide adjuvant (EDV-COVID-αGC), stimulates an alternate pathway due to dendritic cells (DC) displaying both S-polypeptides and αGC thereby recruiting and activating iNKT cells with release of IFNγ. This triggers DC activation/maturation, activation of follicular helper T cells (TFH), cognate help to B cells with secretion of a cytokine milieu promoting B cell maturation, somatic hypermutation in germinal centers to result in high affinity antibodies. Surrogate virus neutralization tests show 90-100% neutralization of ancestral and early VOC in mice and human trial volunteers. EDV-COVID-αGC as a third dose booster neutralized Omicron BA. 4/5. Serum and PBMC analyses reveal long lasting S-specific memory B and T cells. In contrast, control EDVs lacking αGC, did not engage the iNKT/DC pathway resulting in antibody responses unable to neutralize all VOCs and had a reduced B cell memory. The vaccine is lyophilized, stored and transported at room temperature with a shelf-life of over a year.

Glucose Requirement of Antigen-Specific Autoreactive B Cells and CD4+ T Cells.

The activation of lymphocytes in patients with lupus and in mouse models of the disease is coupled with an increased cellular metabolism in which glucose plays a major role. The pharmacological inhibition of glycolysis with 2-deoxy-d-glucose (2DG) reversed the expansion of follicular helper CD4+ T cells and germinal center B cells in lupus-prone mice, as well as the production of autoantibodies. The response of foreign Ags was however not affected by 2DG in these mice, suggesting that B and CD4+ T cell activation by autoantigens is uniquely sensitive to glycolysis. In this study, we tested this hypothesis with monoclonal B cells and CD4+ T cells specific for lupus-relevant autoantigens. AM14 Vκ8R (AM14) transgenic B cells are activated by IgG2a/chromatin immune complexes and they can receive cognate help from chromatin-specific 13C2 CD4+ T cells. We showed that activation of AM14 B cells by their cognate Ag PL2-3 induced glycolysis, and that the inhibition of glycolysis reduced their activation and differentiation into Ab-forming cells, in the absence or presence of T cell help. The dependency of autoreactive B cells on glycolysis is in sharp contrast with the previously reported dependency of 4-hydroxy-3-nitrophenyl acetyl-specific B cells on fatty acid oxidation. Contrary to AM14 B cells, the activation and differentiation of 13C2 T cells into follicular helper CD4+ T cells was not altered by 2DG, which differs from polyclonal CD4+ T cells from lupus-prone mice. These results further define the role of glycolysis in the production of lupus autoantibodies and demonstrate the need to evaluate the metabolic requirements of Ag-specific B and T cells.

CD4 T cell epitope abundance in ferritin core potentiates responses to hemagglutinin nanoparticle vaccines

Nanoparticle vaccines based on H. pylori ferritin are increasingly used as a vaccine platform for many pathogens, including RSV, influenza, and SARS-CoV-2. They have been found to elicit enhanced, long-lived B cell responses. The basis for improved efficacy of ferritin nanoparticle vaccines remains unresolved, including whether recruitment of CD4 T cells specific for the ferritin component of these vaccines contributes to cognate help in the B cell response. Using influenza HA-ferritin nanoparticles as a prototype, we have performed an unbiased assessment of the CD4 T cell epitope composition of the ferritin particles relative to that contributed by influenza HA using mouse models that express distinct constellations of MHC class II molecules. The role that these CD4 T cells play in the B cell responses was assessed by quantifying follicular helper cells (TFH), germinal center (GC) B cells, and antibody secreting cells. When mice were immunized with equimolar quantities of soluble HA-trimers and HA-Fe nanoparticles, HA-nanoparticle immunized mice had an increased overall abundance of TFH that were found to be largely ferritin-specific. HA-nanoparticle immunized mice had an increased abundance of HA-specific isotype-switched GC B cells and HA-specific antibody secreting cells (ASCs) relative to mice immunized with soluble HA-trimers. Further, there was a strong, positive correlation between CD4 TFH abundance and GC B cell abundance. Thus, availability of helper CD4 T cell epitopes may be a key additional mechanism that underlies the enhanced immunogenicity of ferritin-based HA-Fe-nanoparticle vaccines.

AVAILABILITY OF LABORATORY FACILITIES ON STUDENTS’ PERFORMANCE IN UPPER BASIC SCHOOLS IN KWARA STATE, NIGERIA

The study was carried out on the availability of laboratory facilities in teaching of Basic Science on the Students’ academic performance in Upper Basic Schools, Kwara State, Nigeria. This target population for the study was all Basic Science Teachers in Kwara State, Nigeria, four hundred and sixty-nine (469) Public Upper Basic Schools and three hundred and sixty two (362) private schools are available in the study area. The researcher designed teachers' questionnaire and was administered to two hundred and thirty six (236) Basic science teachers that were selected from forty-seven Upper Basic Schools (47) from both public and private schools in Kwara State. Researcher-designed validated questionnaire was used to extract data from the respondents on the teachers 'influence on the performance of students in Upper Basic Schools. Three research questions were raised with two hypotheses which were tested. Percentage and t-test statistics were used to analyze the facts collected. The finding showed that influence of Basic science teachers on the performance of students in Upper Basic Schools in Kwara State, Nigeria was significantly. It was also significant based on gender and on year teaching experience of Basic science teachers. According to the findings, it is suggested that; the educational authorities and the school system should encourage the use of available resources by providing for them, the necessary materials that will influence Basic Science performance and enhance students learning. Basic Science teachers should re-assess their classroom instructional practice because there is a need for them to shift from instructional practice that will give the male and female teachers’ equal opportunities to excel in instructional activities. The less-experienced Basic Science teachers should be allowed for cognate experience and help encourage the experience to acquire more experience.

The immunosenescence-related factor DOCK11 is involved in secondary immune responses of B cells

BackgroundMemory B cells are an antigen-experienced B-cell population with the ability to rapidly differentiate into antibody-producing cells by recall responses. We recently found that dedicator of cytokinesis 11 (DOCK11) contributes to the expansion of antigen-specific populations among germinal center B cells upon immunization. In comparison, limited information is available on the contribution of DOCK11 to secondary humoral immune responses.ResultsIn this study, effects of the DOCK11 deficiency in B cells were examined on secondary immune responses to protein antigen. The lack of DOCK11 in B cells resulted in the impaired induction of antibody-producing cells upon secondary immunization with protein antigen. DOCK11 was dispensable for the recall responses of antigen-experienced B cells, as demonstrated by the comparable induction of antibody-producing cells in mice given transfer of antigen-experienced B cells with no DOCK11 expression. Instead, the lack of DOCK11 in B cells resulted in the impaired secondary immune responses in a B cell-extrinsic manner, which was recovered by the adoptive transfer of cognate T cells.ConclusionsWe addressed that intrinsic and extrinsic effects of DOCK11 expression in B cells may contribute to secondary humoral immune responses in manner of the induction of cognate T-cell help.

A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice

ABSTRACT Antigen-encoding, lipoplex-formulated RNA (RNA-LPX) enables systemic delivery to lymphoid compartments and selective expression in resident antigen-presenting cells. We report here that the rejection of CT26 tumors, mediated by local radiotherapy (LRT), is further augmented in a CD8+ T cell-dependent manner by an RNA-LPX vaccine that encodes CD4+ T cell-recognized neoantigens (CD4 neoantigen vaccine). Whereas CD8+ T cells induced by LRT alone were primarily directed against the immunodominant gp70 antigen, mice treated with LRT plus the CD4 neoantigen vaccine rejected gp70-negative tumors and were protected from rechallenge with these tumors, indicating a potent poly-antigenic CD8+ T cell response and T cell memory. In the spleens of CD4 neoantigen-vaccinated mice, we found a high number of activated, poly-functional, Th1-like CD4+ T cells against ME1, the immunodominant CD4 neoantigen within the poly-neoantigen vaccine. LRT itself strongly increased CD8+ T cell numbers and clonal expansion. However, tumor infiltrates of mice treated with CD4 neoantigen vaccine/LRT, as compared to LRT alone, displayed a higher fraction of activated gp70-specific CD8+ T cells, lower PD-1/LAG-3 expression and contained ME1-specific IFNγ+ CD4+ T cells capable of providing cognate help. CD4 neoantigen vaccine/LRT treatment followed by anti-CTLA-4 antibody therapy further enhanced the efficacy with complete remission of gp70-negative CT26 tumors and survival of all mice. Our data highlight the power of combining synergistic modes of action and warrants further exploration of the presented treatment schema.

Induction of Activated T Follicular Helper Cells Is Critical for Anti-FVIII Inhibitor Development in Hemophilia a Mice

The development of neutralizing anti-FVIII antibodies (inhibitors) is one major complication of FVIII protein replacement therapy in hemophilia A patients. While multiple lines of evidence indicate that the immune response against FVIII is CD4 T cell-dependent, the role of T follicular helper (TFH) cells, a newly identified subset of CD4 T cells, in FVIII inhibitor development is unknown. TFH cells are a critical player in germinal center formation, which provide cognate help to B cells and are fundamentally required for the generation of T cell-dependent B cell responses. Here we explored the activation and induction of TFH cells and their roles in anti-FVIII inhibitor production in FVIII-immunized mice. We first confirmed that inhibitor development depends on CD4 T cells as depletion of CD4 T cells during FVIII immunization in FVIIInull mice prevents inhibitor production. We then characterized the features of activated TFH cells in the spleen of immunized FVIIInull mice by flow cytometry analysis. Activated TFH cells were defined as CD4+Foxp3-CD44+CD62L-CXCR5+PD-1+. These cells express high levels of transcription factors BCL6, ICOS, and CD40L. We showed for the first time that intravenous FVIII immunization induced activation and accumulation and/or expansion of TFH cells in the spleen of FVIIInull mice. The percentage of CXCR5hiPD-1hi TFH cells within the effector CD4 population and the absolute numbers of activated TFH cells per spleen significantly increased in inhibitor-producing mice compared to saline-treated controls and non-inhibitor-producing mice (19.6 ± 1.6 %, 8.1 ± 1.2%, and 7.6 ± 1.4%, respectively; 14.4 ± 2.0×104, 3.55 ± 0.8×104, and 3.5 ± 0.9×104, respectively). There was no TFH cell expansion observed in other secondary lymphoid organs (mesenteric and inguinal lymph nodes), suggesting that the spleen is the primary site for TFH activation when FVIII is administered intravenously. Our results showed that FVIII inhibitor-producing mice had increased GL-7+germinal center TFH cells together with increased germinal center formation in response to FVIII immunization and the emergence of TFH cells correlated with titers of anti-FVIII inhibitors. This indicates that a functional relationship exists between TFH cell activation and FVIII inhibitor production after FVIII immunization. To determine the extent to which the anti-FVIII inhibitor development is related to CXCR5+ TFH cells, we used a mixed BM chimera model consisting of a CD4 T cell-specific CXCR5 deficiency (CD4-CXCR5-/-). Compared with CD4-CXCR5+/+ control mice, there was a significant decrease in the inhibitor titer in CD4-CXCR5-/- mice after FVIII immunization (111.7 ± 46.2 vs 4.43 ± 3.53 BU/ml, respectively). Our results showed that CXCR5+/+ TFH cell-specific deletion impaired anti-FVIII inhibitor production, confirming the essential role of CXCR5+/+ TFH cells for the generation of FVIII-neutralizing antibodies. To examine specificity of TFH cell responses after FVIII immunization, we used an ex vivo T-cell proliferation assay. In vitro FVIII restimulation induced the antigen-specific proliferation of splenic CD4 T cells from FVIII-primed FVIIInull mice and those proliferating cells expressed the TFH hallmark transcription factor BCL6. These results demonstrated that antigen-specific TFH cells were induced after FVIII immunization and those cells could specifically respond to FVIII upon restimulation. To evaluate the FVIII-specific memory TFH cell responses in FVIIInull mice, matched pairs of FVIII-primed mice with similar inhibitor titers were rechallenged with FVIII antigen in vivo 2 months after the last immunization. The absolute numbers of TFH cells per spleen in FVIII rechallenged animals were significantly higher than those obtained from saline-injected primed mice (36.7 ± 11 ×104 vs 14.8 ± 3.8 ×104, respectively). These data suggest that memory FVIII-specific TFH cells are persistent which can induce efficient recall TFH responses after FVIII rechallenge. Together, our results demonstrate that the induction of activated TFH cells in FVIIInull mice is critical for FVIII inhibitor development, suggesting that inhibition of FVIII-specific TFH cell activation might be a promising strategy to prevent anti-FVIII inhibitor formation in hemophilia A patients. Disclosures No relevant conflicts of interest to declare.

Innate B Cells: the Archetype of Protective Immune Cells.

The innate B cell (IBC) population is heterogeneous and involved in the primary immune response. IBC functions include a high ability to produce natural antibodies with IgM isotype, the elimination of apoptotic cells, and a capacity to be cognate help to T cells. Among IBC subsets, B-1 cells and marginal zone B cells are the main producers of IgM, act as rapid immune responders that may relocate to follicular lymphoid and differentiate to cytokine and antibody-secreting cells shortly after infection. IBCs functions are highly dependent on their localization site and the nature of their B cell receptor repertoire, suggesting a high plasticity range of different immune responses. In this review, we will describe the nature and functions of the different innate-like B cell subsets, first in mice and then in humans. Besides this, we will emphasize the strong ability of these cells to undertake different protective functions from the first line of defense against pathogens to the regulatory role of the broader immune response.

Quantifying in situ adaptive immune cell cognate interactions in humans.

Two-photon excitation microscopy (TPEM) has revolutionized our understanding of adaptive immunity. However, TPEM usually requires animal models and is not amenable to the study of human disease. Recognition of antigen by T cells requires cell contact and is associated with changes in T cell shape. We postulated that by capturing these features in fixed-tissue samples, we could quantify in situ adaptive immunity. Therefore, we used a deep convolutional neural network to identify fundamental distance and cell shape features associated with cognate help (Cell Distance Mapping, CDM). In mice, CDM was comparable to TPEM for discriminating cognate from non-cognate T cell:dendritic cell (DC) interactions. In human lupus nephritis, CDM confirmed that myeloid DCs present antigen to CD4+ T cells and identified plasmacytoid DCs as an important antigen-presenting cell. These data reveal a new approach to study human in situ adaptive immunity broadly applicable to autoimmunity, infection, and cancer.

Germinal center humoral autoimmunity independently mediates progression of allograft vasculopathy

The development of humoral autoimmunity following organ transplantation is increasingly recognised, but of uncertain significance. We examine whether autoimmunity contributes independently to allograft rejection.In a MHC class II-mismatched murine model of chronic humoral rejection, we report that effector antinuclear autoantibody responses were initiated upon graft-versus-host allorecognition of recipient B cells by donor CD4 T-cells transferred within heart allografts. Consequently, grafts were rejected more rapidly, and with markedly augmented autoantibody responses, upon transplantation of hearts from donors previously primed against recipient. Nevertheless, rejection was dependent upon recipient T follicular helper (TFH) cell differentiation and provision of cognate (peptide-specific) help for maintenance as long-lived GC reactions, which diversified to encompass responses against vimentin autoantigen. Heart grafts transplanted into stable donor/recipient mixed haematopoietic chimeras, or from parental strain donors into F1 recipients (neither of which can trigger host adaptive alloimmune responses), nevertheless provoked GC autoimmunity and were rejected chronically, with rejection similarly dependent upon host TFH cell differentiation.Thus, autoantibody responses contribute independently of host adaptive alloimmunity to graft rejection, but require host TFH cell differentiation to maintain long-lived GC responses. The demonstration that one population of helper CD4 T-cells initiates humoral autoimmunity, but that a second population of TFH cells is required for its maintenance as a GC reaction, has important implications for how autoimmune-related phenomena manifest.

Vaccine Designs Utilizing Invariant NKT-Licensed Antigen-Presenting Cells Provide NKT or T Cell Help for B Cell Responses.

Vaccines against a variety of infectious diseases have been developed and tested. Although there have been some notable successes, most are less than optimal or have failed outright. There has been discussion about whether either B cells or dendritic cells (DCs) could be useful for the development of antimicrobial vaccines with the production of high titers of antibodies. Invariant (i)NKT cells have direct antimicrobial effects as well as adjuvant activity, and iNKT-stimulated antigen-presenting cells (APCs) can determine the form of the ensuing humoral and cellular immune responses. In fact, upon activation by ligand, iNKT cells can stimulate both B cells and DCs as via either cognate or non-cognate help. iNKT-licensed DCs generate antigen-specific follicular helper CD4+ T cells, which in turn stimulate B cells, thus leading to long-term antigen-specific antibody production. Follicular helper iNKT cell-licensed B cells generally produce rapid, but short-term antibody. However, under some conditions in the presence of Th cells, the antibody production can be prolonged. With regards to humoral immunity, the quality and quantity of Ab produced depends on the APC type and the form of the vaccine. In terms of cellular immunity and, in particular, the induction of cytotoxic CD8+ T cells, iNKT-licensed DCs show prominent activity. In this review, we discuss differences in iNKT-stimulated APC types and the quality of the ensuing immune response, and also discuss their application in vaccine models to develop successful preventive immunotherapy against infectious diseases.

Memory Follicular Helper Invariant NKT Cells Recognize Lipid Antigens on Memory B Cells and Elicit Antibody Recall Responses.

Invariant NKT (iNKT) cells have been shown to help B cells in a cognate or noncognate manner; however, whether cognate iNKT cell help induces B cell memory responses remains controversial, and the underlying mechanisms are still unclear. In this study, we demonstrated that, in the absence of follicular helper T cells, cognate iNKT cell help could promote B cell memory responses in mice that were dependent on the formation of memory follicular helper iNKT (iNKTFH) cells and their interactions with memory B cells in recall responses. Generation of memory iNKTFH cells required lipid Ag presentation by dendritic cells but not by B cells. Upon rechallenge, memory iNKTFH cells recognized lipid Ags presented by memory B cells, which recalled iNKTFH effector cells and elicited B cell memory responses. However, LPS, which promoted the synthesis of self-lipids, failed to elicit recall responses in the absence of exogenous lipid Ags.

Potential Epigenetic Regulation in the Germinal Center Reaction of Lymphoid Tissues in HIV/SIV Infection.

The production of high-affinity and broadly neutralizing antibodies plays a key role in the defense against pathogens. These antibody responses require effective germinal center (GC) reaction within anatomical niches of GCs, where follicular helper T (Tfh) cells provide cognate help to B cells for T cell-dependent antibody responses. Emerging evidences indicate that GC reaction in normal state and perhaps establishment of latent Tfh cell reservoir in HIV/SIV infection are tightly regulated by epigenetic histone modifications, which are responsible for activating or silencing chromatin. A better understanding of the mechanisms behind GC responses at cellular and molecular levels thus provides necessary knowledge for vaccination and immunotherapy. In this review, we discussed the epigenetic regulation of GC responses, especially for GC B and Tfh cell under normal state or HIV/SIV infection.

The Old One-Two: Solving the Mystery of Cognate Help.

The pivotal findings reported by Noelle et al. ([1][1]) in 1992 resolved a puzzle that had been 40 years in the making. In the mid-20th century, seminal studies from Owen ([2][2]), Medawar and colleagues ([3][3], [4][4]) and Burnet ([5][5]) established the concept of an immunological self, forcing

Characterization of T follicular helper cells in allogeneic normal pregnancy and PDL1 blockage-induced abortion.

A deeper understanding of the immunological events during pregnancy will provide novel insights into the pathogenesis of pregnancy complications. The fundamental function of T follicular helper (Tfh) cells is to provide cognate help to B cells. Dysregulations of Tfh-cell function and/or development can result in various immunological diseases. However, the role and characteristics of Tfh cells during pregnancy remain unknown. Herein, an allogeneic-normal-pregnant mouse model was used, and we found that the CD4+ T cells residing at the uterus and placenta (UP) displayed a Tfh-like phenotype; and the UP-derived CD4+CXCR5hiPD-1hi and CD4+CXCR5hiICOShi Tfh cells, which showed a memory/activation phenotype, reached their peak at mid-pregnancy. These Tfh cells were located abundantly in the uterus at mid-pregnancy, but greatly increased in the placenta at late-pregnancy. Furthermore, increased foetal resorption by PDL1 blockade correlated with enhanced accumulation of Tfh cells and upregulated expressions of ICOS and PD-1 on these cells. Collectively, our findings are the first to indicate that an adequate and balanced accumulation of Tfh cells during gestation is likely to help maintaining a successful pregnancy, whereas an excessively high level of these cells could lead to abortion.

A Special Connection between γδ T Cells and Natural Antibodies?

Natural antibodies (NAbs) play an important role in early host defense, autophagy and tissue remodeling, and in immune regulation. They arise spontaneously (without specific immunization), and are already present at birth. NAbs are produced by B1 B cells, MZ B cells and other B cell types. They include all major Ig subclasses but IgM antibodies are prevalent, especially early in development. NAbs may be poly-specific, recognize particular auto-antigens, or detect neo-determinants such as those exposed during apoptosis or generated by oxidation. NAbs do not require cognate T cell help but depend on soluble mediators produced by T cells. Our recent studies suggest that γδ T cells may have a special relationship with NAbs, and play a prominent role in their regulation, in part through the fine-tuning of IL-4 levels. The spontaneously activated state of these cells likely enables their cytokine production and other functions in the absence of external stimulation. Ontogenetically, the earlier arising γδ T cells are better positioned than αβ T cells to shape the developing repertoire of NAbs. Intriguingly, ligand specificities of NAbs and γδ T cell receptors appear to be overlapping, perhaps allowing γδ cognate help for certain NAb specificities. Via NAbs, γδ T cells could exert a regulatory influence on numerous processes in health and disease.

Augmentation of Recipient Adaptive Alloimmunity by Donor Passenger Lymphocytes within the Transplant.

SummaryChronic rejection of solid organ allografts remains the major cause of transplant failure. Donor-derived tissue-resident lymphocytes are transferred to the recipient during transplantation, but their impact on alloimmunity is unknown. Using mouse cardiac transplant models, we show that graft-versus-host recognition by passenger donor CD4 T cells markedly augments recipient cellular and humoral alloimmunity, resulting in more severe allograft vasculopathy and early graft failure. This augmentation is enhanced when donors were pre-sensitized to the recipient, is dependent upon avoidance of host NK cell recognition, and is partly due to provision of cognate help for allo-specific B cells from donor CD4 T cells recognizing B cell MHC class II in a peptide-degenerate manner. Passenger donor lymphocytes may therefore influence recipient alloimmune responses and represent a therapeutic target in solid organ transplantation.

Cognate interaction with iNKT cells expands IL-10–producing B regulatory cells

Successful induction of B-cell activation and memory depends on help from CD4+ T cells. Invariant natural killer T (iNKT) cells (glycolipid-specific, CD1d-restricted innate lymphocytes) provide both cognate (direct) and noncognate (indirect) helper signals to enhance B-cell responses. Both forms of iNKT-cell help induce primary humoral immune responses, but only noncognate iNKT-cell help drives humoral memory and plasma cells. Here, we show that iNKT cognate help for B cells is fundamentally different from the help provided by conventional CD4+ T cells. Cognate iNKT-cell help drives an early, unsustained germinal center B-cell expansion, less reduction of T follicular regulatory cells, an expansion of marginal zone B cells, and early increases in regulatory IL-10-producing B-cell numbers compared with noncognate activation. These results are consistent with a mechanism whereby iNKT cells preferentially provide an innate form of help that does not generate humoral memory and has important implications for the application of glycolipid molecules as vaccine adjuvants.

Type II NKT-TFH cells against Gaucher lipids regulate B-cell immunity and inflammation

AbstractChronic inflammation including B-cell activation is commonly observed in both inherited (Gaucher disease [GD]) and acquired disorders of lipid metabolism. However, the cellular mechanisms underlying B-cell activation in these settings remain to be elucidated. Here, we report that β-glucosylceramide 22:0 (βGL1-22) and glucosylsphingosine (LGL1), 2 major sphingolipids accumulated in GD, can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Human βGL1-22– and LGL1-reactive CD1d tetramer–positive T cells have a distinct T-cell receptor usage and genomic and cytokine profiles compared with the classical type I NKT cells. In contrast to type I NKT cells, βGL1-22– and LGL1-specific NKT cells constitutively express T-follicular helper (TFH) phenotype. Injection of these lipids leads to an increase in respective lipid-specific type II NKT cells in vivo and downstream induction of germinal center B cells, hypergammaglobulinemia, and production of antilipid antibodies. Human βGL1-22– and LGL1-specific NKT cells can provide efficient cognate help to B cells in vitro. Frequency of LGL1-specific T cells in GD mouse models and patients correlates with disease activity and therapeutic response. Our studies identify a novel type II NKT-mediated pathway for glucosphingolipid-mediated dysregulation of humoral immunity and increased risk of B-cell malignancy observed in metabolic lipid disorders.