Search

Infections during pregnancy are known to trigger alterations in offspring immunity, often leading to increased disease susceptibility. Maternal helminth infections correlate with lower Ab titers to certain childhood immunizations and putative decreased vaccine efficacy. The mechanisms that underlie how maternal infection blunts offspring humoral responses are unclear. Using our murine model of maternal schistosomiasis, we found that maternal helminth infection decreases the germinal center response of all offspring to tetanus immunization. However, only male offspring have defects in memory B cell and long-lived plasma cell generation. We found this sex-specific aberration begins during B cell development within the bone marrow via alteration of the IL-7 niche and persists throughout antigenic activation in the germinal center in the periphery. Critically, these defects in males are cell intrinsic, persisting following adoptive transfer to control male pups. Together, these data show that maternal infections can alter both the bone marrow microenvironment and the development of B lymphocytes in a sex-specific manner. This study correlates maternal infection induced defects in early life B cell development with ineffective Ab responses after vaccination., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Current influenza vaccine strategies have yet to overcome significant obstacles, including rapid antigenic drift of seasonal influenza viruses, in generating efficacious long-term humoral immunity. Due to the necessity of germinal center formation in generating long-lived high affinity antibodies, the germinal center has increasingly become a target for the development of novel or improvement of less-efficacious vaccines. However, there remains a major gap in current influenza research to effectively target T follicular helper cells during vaccination to alter the germinal center reaction. In this study, we used a heterologous infection or immunization priming strategy to seed an antigen-specific memory CD4+ T cell pool prior to influenza infection in mice to evaluate the effect of recalled memory T follicular helper cells in increased help to influenza-specific primary B cells and enhanced generation of neutralizing antibodies. We found that heterologous priming with intranasal infection with acute lymphocytic choriomeningitis virus (LCMV) or intramuscular immunization with adjuvanted recombinant LCMV glycoprotein induced increased antigen-specific effector CD4+ T and B cellular responses following infection with a recombinant influenza strain that expresses LCMV glycoprotein. Heterologously primed mice had increased expansion of secondary Th1 and Tfh cell subsets, including increased CD4+ TRM cells in the lung. However, the early enhancement of the germinal center cellular response following influenza infection did not impact influenza-specific antibody generation or B cell repertoires compared to primary influenza infection. Overall, our study suggests that while heterologous infection or immunization priming of CD4+ T cells is able to enhance the early germinal center reaction, further studies to understand how to target the germinal center and CD4+ T cells specifically to increase long-lived antiviral humoral immunity are needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sircy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Although T cells are encephalitogenic during demyelinating disease, B cell-depleting therapies are a successful treatment for patients with multiple sclerosis. Murine models of demyelinating disease utilizing myelin epitopes, such as myelin oligodendrocyte glycoprotein (MOG)35-55, induce a robust CD4 T cell response but mitigate the contribution of pathological B cells. This limits their efficacy for investigating how B cell depletion affects T cells. Furthermore, induction of experimental autoimmune encephalomyelitis with a single CD4 T cell epitope does not reflect the breadth of epitopes observed in the clinic. To better model the adaptive immune response, mice were immunized with the full-length MOG protein or the MOG1-125 extracellular domain (ECD) and compared with MOG35-55. Mature MOG-reactive B cells were generated only by full-length MOG or ECD. The CNS-localized T cell response induced by full-length MOG is characterized by a reduction in frequency and the percentage of low-affinity T cells with reactivity toward the core epitope of MOG35-55. B cell depletion with anti-CD20 before full-length MOG-induced, but not ECD-induced, demyelinating disease restored T cell reactivity toward the immunodominant epitope of MOG35-55, suggesting the B cell-mediated control of encephalitogenic epitopes. Ultimately, this study reveals that anti-CD20 treatment can influence T cell epitopes found in the CNS during demyelinating disease., (Copyright © 2024 The Authors.)

Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with inferior overall survival after ICB. Mechanistically, these phenotypes are at least partially explained by ARF6-dependent recycling, which controls plasma membrane density of the interferon-gamma receptor. Collectively, our findings reveal the importance of endomembrane trafficking in outfitting tumour cells with the ability to shape their immune microenvironment and respond to immunotherapy., (© 2024. The Author(s).)

Maternal infection during pregnancy is known to alter the development and function of offspring's immune system, leading to inappropriate immune responses to common childhood infections and immunizations. Although this is an expanding field, maternal parasitic infections remain understudied. Millions of women of reproductive age are currently at risk for parasitic infection, whereas many pregnant, chronically infected women are excluded from mass drug administration due partially to a lack of resources, as well as fear of unknown adverse fetal developmental outcomes. In areas endemic for multiple parasitic infections, such as sub-Saharan Africa, there are increased rates of morbidity and mortality for various infections during early childhood in comparison with nonendemic areas. Despite evidence supporting similar immunomodulatory effects between various parasite species, there is no clear mechanistic understanding of how maternal infection reprograms offspring immunity. This brief review will compare the effects of selected maternal parasitic infections on offspring immunity., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes that aid in protection against bacterial pathogens at mucosal surfaces through the release of inflammatory cytokines and cytotoxic molecules. Recent evidence suggests that MAIT cells can also provide B cell help. In this study, we describe a population of CXCR5 + T follicular helper (Tfh)–like MAIT cells (MAITfh) that have the capacity to provide B cell help within mucosal lymphoid organs. MAITfh cells are preferentially located near germinal centers in human tonsils and express the classical Tfh-associated transcription factor, B cell lymphoma 6 (BCL-6), the costimulatory markers inducible T cell costimulatory (ICOS) and programmed death receptor 1 (PD-1), and interleukin-21 (IL-21). We demonstrate the ability of MAIT cells to provide B cell help in vivo after mucosal challenge with Vibrio cholerae . Specifically, we show that adoptive transfer of MAIT cells into αβ T cell–deficient mice promoted B cell differentiation and increased serum V. cholerae –specific IgA responses. Our data demonstrate the capacity of MAIT cells to participate in adaptive immune responses and suggest that MAIT cells may be potential targets for mucosal vaccines.

Epidemiological studies have identified a correlation between maternal helminth infections and reduced immunity to some early childhood vaccinations, but the cellular basis for this is poorly understood. Here, we investigated the effects of maternal Schistosoma mansoni infection on steady-state offspring immunity, as well as immunity induced by a commercial tetanus/diphtheria vaccine using a dual IL-4 reporter mouse model of maternal schistosomiasis. We demonstrate that offspring born to S. mansoni infected mothers have reduced circulating plasma cells and peripheral lymph node follicular dendritic cells at steady state. These reductions correlate with reduced production of IL-4 by iNKT cells, the cellular source of IL-4 in the peripheral lymph node during early life. These defects in follicular dendritic cells and IL-4 production were maintained long-term with reduced secretion of IL-4 in the germinal center and reduced generation of TFH, memory B, and memory T cells in response to immunization with tetanus/diphtheria. Using single-cell RNASeq following tetanus/diphtheria immunization of offspring, we identified a defect in cell-cycle and cell-proliferation pathways in addition to a reduction in Ebf-1, a key B-cell transcription factor, in the majority of follicular B cells. These reductions are dependent on the presence of egg antigens in the mother, as offspring born to single-sex infected mothers do not have these transcriptional defects. These data indicate that maternal schistosomiasis leads to long-term defects in antigen-induced cellular immunity, and for the first time provide key mechanistic insight into the factors regulating reduced immunity in offspring born to S. mansoni infected mothers., Competing Interests: The authors have declared that no competing interests exist.

Macrophages have a defined role in the pathogenesis of metabolic disease and cholesterol metabolism where alternative activation of macrophages is thought to be beneficial to both glucose and cholesterol metabolism during high fat diet induced disease. It is well established that helminth infection protects from metabolic disease, but the mechanisms underlying protection are not well understood. Here, we investigated the effects of Schistosoma mansoni infection and cytokine activation in the metabolic signatures of bone marrow derived macrophages using an approach that integrated transcriptomics, metabolomics, and lipidomics in a metabolic disease prone mouse model. We demonstrate that bone marrow derived macrophages (BMDM) from S. mansoni infected male ApoE-/- mice have dramatically increased mitochondrial respiration compared to those from uninfected mice. This change is associated with increased glucose and palmitate shuttling into TCA cycle intermediates, increased accumulation of free fatty acids, and decreased accumulation of cellular cholesterol esters, tri and diglycerides, and is dependent on mgll activity. Systemic injection of IL-4 complexes is unable to recapitulate either reductions in systemic glucose AUC or the re-programing of BMDM mitochondrial respiration seen in infected males. Importantly, the metabolic reprogramming of male myeloid cells is transferrable via bone marrow transplantation to an uninfected host, indicating maintenance of reprogramming in the absence of sustained antigen exposure. Finally, schistosome induced metabolic and bone marrow modulation is sex-dependent, with infection protecting male, but not female mice from glucose intolerance and obesity. Our findings identify a transferable, long-lasting sex-dependent reprograming of the metabolic signature of macrophages by helminth infection, providing key mechanistic insight into the factors regulating the beneficial roles of helminth infection in metabolic disease., Competing Interests: The authors have declared that no competing interests exist.

IL-4 is critical for differentiation of Th2 cells and antibody isotype switching, but our work demonstrated that it is produced in the peripheral LN under both Type 2, and Type 1 conditions, raising the possibility of other functions. We found that IL-4 is vital for proper positioning of hematopoietic and stromal cells in steady state, and the lack of IL-4 or IL-4Rα correlates with disarrangement of both follicular dendritic cells and CD31 + endothelial cells. We observed a marked disorganization of B cells in these mice, suggesting that the lymphocyte-stromal cell axis is maintained by the IL-4 signaling pathway. This study showed that absence of IL-4 correlates with significant downregulation of Lymphotoxin alpha (LTα) and Lymphotoxin beta (LTβ), critical lymphokines for the development and maintenance of lymphoid organs. Moreover, immunization of IL-4 deficient mice with Type 2 antigens failed to induce lymphotoxin production, LN reorganization, or germinal center formation, while this process is IL-4 independent following Type 1 immunization. Additionally, we found that Type 1 antigen mediated LN reorganization is dependent on IFN-γ in the absence of IL-4. Our findings reveal a role of IL-4 in the maintenance of peripheral lymphoid organ microenvironments during homeostasis and antigenic challenge., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hepatic macrophages play an essential role in the granulomatous response to infection with the parasitic helminth Schistosoma mansoni , but the transcriptional changes that underlie this effect are poorly understood. To explore this, we sorted the two previously recognized hepatic macrophage populations (perivascular and Kupffer cells) from naïve and S. mansoni -infected male mice and performed microarray analysis as part of the Immunological Genome Project. The two hepatic macrophage populations exhibited remarkably different genomic profiles. However, this diversity was substantially reduced following infection with S. mansoni , and in fact, both populations demonstrated increases in transcripts of the monocyte lineage, suggesting that both populations may be replenished by monocytes following infection. Pathway analysis showed a profound alteration in global metabolic pathways, including changes to phospholipid and cholesterol metabolism, as well as amino acid biosynthesis and glucagon signaling. These changes suggest a possible mechanism for the previously reported athero-protective effects of S. mansoni infection. Indeed, we find that male ApoE null mice fed a high-fat diet in combination with S. mansoni infection have reduced plaque area and increased glucose tolerance as compared to control mice. Transcript analysis of infected and control high-fat diet fed ApoE -/- mice confirm that ApoC1, Psat1 , and Gys1 are all altered by infection, suggesting that altered hepatic macrophage metabolism is associated with S. mansoni - induced protection from hyperlipidemia, atherosclerosis, and glucose intolerance. These results suggest a previously unknown and unreported role of hepatic macrophages in the modulation of whole body lipid and glucose metabolism during infection and provide a template for examining the role of immunomodulation on the long-term metabolism of the host.

Low vitamin D status potentiates experimental colitis, but the vitamin D-responsive cell in colitis has not been defined. We hypothesized that vitamin D has distinct roles in colonic epithelial cells and in nonepithelial cells during colitis. We tested this hypothesis by using mice with vitamin D receptor (VDR) deletion from colon epithelial cells (CEC-VDRKO) or nonintestinal epithelial cells (NEC-VDRKO). Eight-week-old mice were treated with 1.35% dextran sulfate sodium (DSS) for 5 days and then euthanized 2 or 10 days after removal of DSS. DSS induced body weight loss and increased disease activity index and spleen size. This response was increased in NEC-VDRKO mice but not CEC-VDRKO mice. DSS-induced colon epithelial damage and immune cell infiltration scores were increased in both mouse models. Although the epithelium healed between 2 and 10 days after DSS administration in control and CEC-VDRKO mice, epithelial damage remained high in NEC-VDRKO mice 10 days after removal of DSS, indicating delayed epithelial healing. Gene expression levels for the proinflammatory, M1 macrophage (Mɸ) cytokines tumor necrosis factor-α, nitric oxide synthase 2, and interleukin-1β were significantly elevated in the colon of NEC-VDRKO mice at day 10. In vitro experiments in murine peritoneal Mɸs demonstrated that 1,25 dihydroxyvitamin D directly inhibited M1 polarization, facilitated M2 polarization, and regulated Mɸ phenotype switching toward the M2 and away from the M1 phenotype. Our data revealed unique protective roles for vitamin D signaling during colitis in the colon epithelium as well as nonepithelial cells in the colon microenvironment (i.e., modulation of Mɸ biology)., (Copyright © 2017 Endocrine Society.)

CD8α(+) and CD103(+) dendritic cells (DCs) play a central role in the development of type 1 immune responses. However, their role in type 2 immunity remains unclear. We examined this issue using Batf3(-/-) mice, in which both of these DC subsets are missing. We found that Th2 cell responses, and related events such as eosinophilia, alternative macrophage activation, and immunoglobulin class switching to IgG1, were enhanced in Batf3(-/-) mice responding to helminth parasites. This had beneficial or detrimental consequences depending on the context. For example, Batf3 deficiency converted a normally chronic intestinal infection with Heligmosomoides polygyrus into an infection that was rapidly controlled. However, liver fibrosis, an IL-13-mediated pathological consequence of wound healing in chronic schistosomiasis, was exacerbated in Batf3(-/-) mice infected with Schistosoma mansoni. Mechanistically, steady-state production of IL-12 by migratory CD103(+) DCs, independent of signals from commensals or TLR-initiated events, was necessary and sufficient to exert the suppressive effects on Th2 response development. These findings identify a previously unrecognized role for migratory CD103(+) DCs in antagonizing type 2 immune responses., (© 2016 Everts et al.)

Humoral immunity requires cross-talk between T follicular helper (Tfh) cells and B cells. Nevertheless, a detailed understanding of this intercellular interaction during secondary immune responses is lacking. We examined this by focusing on the response to a soluble, unadjuvanted, pathogen-derived Ag (soluble extract of Schistosoma mansoni egg [SEA]) that induces type 2 immunity. We found that activated Tfh cells persisted for long periods within germinal centers following primary immunization. However, the magnitude of the secondary response did not appear to depend on pre-existing Tfh cells. Instead, Tfh cell populations expanded through a process that was dependent on memory T cells recruited into the reactive LN, as well as the participation of B cells. We found that, during the secondary response, IL-4 was critical for the expansion of a population of plasmablasts that correlated with increased SEA-specific IgG1 titers. Additionally, following immunization with SEA (but not with an Ag that induced type 1 immunity), IL-4 and IL-21 were coproduced by individual Tfh cells, revealing a potential mechanism through which appropriate class-switching can be coupled to plasmablast proliferation to enforce type 2 immunity. Our findings demonstrate a pivotal role for IL-4 in the interplay between T and B cells during a secondary Th2 response and have significant implications for vaccine design., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Nematodes are unable to synthesize fatty acids de novo and must acquire them from the environment or host. It is hypothesized that two unique classes of fatty acid and retinol binding proteins that nematodes produce (fatty acid and retinol binding (FAR) and nematode polyprotein antigen/allergen (NPA)) are used to meet this need. A partial cDNA has been cloned corresponding to four subunits of a putative Ancylostoma ceylanicum NPA (AceNPA). The translated amino acid sequence of AceNPA shares sequence identity with similar proteins from Dictyocaulus viviparus, Ascaris suum, and Ostertagia ostertagi. Immunoblot experiments using a polyclonal anti-AceNPA IgG revealed proteins corresponding to the expected sizes of single, as well as two or three un-cleaved NPA subunits in adult excretory/secretory proteins and soluble adult worm extracts. Immunohistochemistry experiments localize AceNPA to the cuticle, pseudocoelomic space and testes suggesting a role in hookworm biology that is distinct from what has previously been defined for other hookworm lipid binding proteins. A single recombinant subunit of AceNPA (rAceNPAb) demonstrated binding in vitro to fluorescent fatty acids DAUDA, cis-parinaric acid, as well as retinol, at equilibrium dissociation constants in the low micromolar range. Further, in vitro data reveal that rAceNPAb binds fatty acids with chain lengths of C12-C22, with the greatest affinities for arachidonic, linoleic (C18), and eicosapentaenoic (C20) acids., (Copyright © 2014 Elsevier B.V. All rights reserved.)

During infection with the helminth parasite Schistosoma mansoni, Ab regulates hepatic inflammation, and local production of Ig in the liver appears to play a role in this process. Exploring the development of the B cell response during infection, we found that parasite-specific IgG1-secreting plasma cells appeared first in the hepatic and mesenteric lymph nodes (LNs) and then at later times in the spleen, liver, and bone marrow. The LN B cell population peaked between weeks 10 and 12 of infection, and then contracted at a time that coincided with the expansion of the hepatic IgG1(+) B cell compartment, suggesting that B cells migrate from LNs to liver. CXCL9 and -16 expression in the liver increased during the time frame of B cell recruitment. Expression of the CXCL16 receptor CXCR6 was increased on B cells within the hepatic LNs, but not the mesenteric LNs. CXCR3, the receptor for CXCL9, was broadly expressed on IgG1(+) B cells in LNs and liver during infection. Increased hepatic expression of CXCL9 and -16 failed to occur if the IL-10R was blocked in vivo, an intervention associated with decreased liver B cell infiltration and the development of severe disease. Hepatic LN IgG1(+) cells migrated toward CXCL9 and -16 in vitro and to the liver in a pertussis toxin-sensitive fashion. Our data suggest that the coordinated expression of CXCL9 and -16 in the liver and of CXCR6 and CXCR3 on responding B cells within the hepatic LNs underpins establishment of the hepatic B cell infiltrate during chronic schistosomiasis.

In schistosomiasis patients, parasite eggs trapped in hepatic sinusoids become foci for CD4+ T cell-orchestrated granulomatous cellular infiltrates. Since the immune response is unable to clear the infection, the liver is subjected to ongoing cycles of focal inflammation and healing that lead to vascular obstruction and tissue fibrosis. This is mitigated by regulatory mechanisms that develop over time and which minimize the inflammatory response to newly deposited eggs. Exploring changes in the hepatic inflammatory infiltrate over time in infected mice, we found an accumulation of schistosome egg antigen-specific IgG1-secreting plasma cells during chronic infection. This population was significantly diminished by blockade of the receptor for IL-10, a cytokine implicated in plasma cell development. Strikingly, IL-10R blockade precipitated the development of portal hypertension and the accumulation of parasite eggs in the lungs and heart. This did not reflect more aggressive Th2 cell responsiveness, increased hepatic fibrosis, or the emergence of Th1 or Th17 responses. Rather, a role for antibody in the prevention of severe disease was suggested by the finding that pulmonary involvement was also apparent in mice unable to secrete class switched antibody. A major effect of anti-IL-10R treatment was the loss of a myeloid population that stained positively for surface IgG1, and which exhibited characteristics of regulatory/anti-inflammatory macrophages. This finding suggests that antibody may promote protective effects within the liver through local interactions with macrophages. In summary, our data describe a role for IL-10-dependent B cell responses in the regulation of tissue damage during a chronic helminth infection.

Hookworms, bloodfeeding intestinal nematodes, infect nearly one billion people in resource limited countries and are a leading cause of anaemia and malnutrition. Like other nematodes, hookworms lack the capacity to synthesise essential fatty acids de novo and therefore must acquire those from exogenous sources. The cDNA corresponding to a putative Ancylostoma ceylanicum fatty acid and retinol binding protein-1 (AceFAR-1) was amplified from adult hookworm mRNA. Studies using quantitative reverse transcriptase real-time PCR demonstrate that AceFAR-1 transcripts are most abundant in the earliest developmental stages of the parasite, and greater in females than males. Using in vitro assays, the recombinant AceFAR-1 (rAceFAR-1) was shown to bind individual fatty acids with equilibrium dissociation constants in the low micromolar range. The pattern of fatty acid uptake by live adult worms cultured ex vivo was similar to the in vitro binding profile of rAceFAR-1, raising the possibility that the native protein may be involved in acquisition of fatty acids by A. ceylanicum. Animals vaccinated orally with rAceFAR-1 and the mucosal adjuvant cholera toxin exhibited a statistically significant (40-47%) reduction in intestinal worm burden compared with controls immunized with antigen or adjuvant alone. Together, these data suggest a potential role for AceFAR-1 in hookworm biology, making it a potentially valuable target for drug and vaccine development.