Project description:Consecutive exposures to different pathogens are very common and often alter host immune responses. Yet, it remains unknown how a secondary bacterial infection interferes with an ongoing adaptive immune response elicited against primary invading pathogens. Here, we demonstrate that pre-existing germinal center (GC) B cells are incapable of enduring radical metabolic changes induced by recruited Sca-1+ monocytes during Salmonella Typhimurium (STm) infection. GCs-induced by influenza, plasmodium and commensals deteriorated upon STm infection. GC collapse was independent of direct bacterial interactions with B cells, but rather, was induced through recruitment of CCR2-dependent Sca-1+ monocytes. GC collapse was dependent on non-B cell TLR-4, TNFα and IFNγ, which was essential for Sca-1+ monocyte differentiation in the bone-marrow. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon lethal bacterial infection is induced at the expense of antibody-mediated immunity.
Project description:Consecutive exposures to different pathogens are very common and often alter host immune responses. Yet, it remains unknown how a secondary bacterial infection interferes with an ongoing adaptive immune response elicited against primary invading pathogens. Here, we demonstrate that pre-existing germinal center (GC) B cells are incapable of enduring radical metabolic changes induced by recruited Sca-1+ monocytes during Salmonella Typhimurium (STm) infection. GCs-induced by influenza, plasmodium and commensals deteriorated upon STm infection. GC collapse was independent of direct bacterial interactions with B cells, but rather, was induced through recruitment of CCR2-dependent Sca-1+ monocytes. GC collapse was dependent on non-B cell TLR-4, TNFα and IFNγ, which was essential for Sca-1+ monocyte differentiation in the bone-marrow. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon lethal bacterial infection is induced at the expense of antibody-mediated immunity.
Project description:Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation [Bulk RNA-seq]
Project description:Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation [Single-cell RNA-seq]
Project description:Ex vivo engineered three-dimensional organotypic cultures have enabled the real-time study and control of biological functioning of mammalian tissues. Organs of broad interest where its architectural, cellular, and molecular complexity has prevented progress in ex vivo engineering are the secondary immune organs. Ex vivo immune organs can enable mechanistic understanding of the immune system and more importantly, accelerate the translation of immunotherapies as well as a deeper understanding of the mechanisms that lead to their malignant transformation into a variety of B and T cell malignancies. However, till date, no modular ex vivo immune organ has been developed with an ability to control the rate of immune reaction through tunable design parameter. Here we describe a B cell follicle organoid made of nanocomposite biomaterials, which recapitulates the anatomical microenvironment of a lymphoid tissue that provides the basis to induce an accelerated germinal center (GC) reaction by continuously providing extracellular matrix (ECM) and cell-cell signals to naïve B cells. Compared to existing co-cultures, immune organoids provide a control over primary B cell proliferation with ?100-fold higher and rapid differentiation to the GC phenotype with robust antibody class switching.
Project description:Foxp3(+) regulatory T (T(reg)) cells suppress different types of immune responses to help maintain homeostasis in the body. How T(reg) cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of T(reg) cells expressing CXCR5 and Bcl-6 that localize to the germinal centers in mice and humans. The expression of CXCR5 on T(reg) cells depends on Bcl-6. These CXCR5(+)Bcl-6(+) T(reg) cells are absent in the thymus but can be generated de novo from CXCR5(-)Foxp3(+) natural T(reg) precursors. A lack of CXCR5(+) T(reg) cells leads to greater germinal center reactions including germinal center B cells, affinity maturation of antibodies and the differentiation of plasma cells. These results unveil a Bcl-6-CXCR5 axis in T(reg) cells that drives the development of follicular regulatory T (T(FR)) cells that function to inhibit the germinal center reactions.
Project description:IntroductionN-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is mediated by immunoglobulin G (IgG) autoantibodies directed against the NR1 subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1-IgG production and the contribution of germinal center B cells to NR1-IgG levels are unknown.MethodsClinical data and longitudinal paired serum NR1-reactive IgM and IgG levels from 10 patients with NMDAR-antibody encephalitis were determined. Peripheral blood mononuclear cells from these 10 patients, and two available ovarian teratomas, were stimulated with combinations of immune factors and tested for secretion of total IgG and NR1-specific antibodies.ResultsIn addition to disease-defining NR1-IgG, serum NR1-IgM was found in 6 of 10 patients. NR1-IgM levels were typically highest around disease onset and detected for several months into the disease course. Moreover, circulating patient B cells were differentiated into CD19+ CD27++ CD38++ antibody-secreting cells in vitro and, from 90% of patients, secreted NR1-IgM and NR1-IgG. Secreted levels of NR1-IgG correlated with serum NR1-IgG (p?<?0.0001), and this was observed across the varying disease durations, suggestive of an ongoing process. Furthermore, ovarian teratoma tissue contained infiltrating lymphocytes which produced NR1-IgG in culture.InterpretationSerum NR1-IgM and NR1-IgG, alongside the consistent production of NR1-IgG from circulating B cells and from ovarian teratomas suggest that ongoing germinal center reactions may account for the peripheral cell populations which secrete NR1-IgG. Cells participating in germinal center reactions might be a therapeutic target for the treatment of NMDAR-antibody encephalitis. Ann Neurol 2018;83:553-561.
Project description:Gut microbiota educate the local and distal immune system in early life to imprint long-term immunological outcomes while maintaining the capacity to dynamically modulate the local mucosal immune system throughout life. It is unknown whether gut microbiota provide signals that dynamically regulate distal immune responses following an extra-gastrointestinal infection. We show here that gut bacteria composition correlated with the severity of malaria in children. Using the murine model of malaria, we demonstrate that parasite burden and spleen germinal center reactions are malleable to dynamic cues provided by gut bacteria. Whereas antibiotic-induced changes in gut bacteria have been associated with immunopathology or impairment of immunity, the data demonstrate that antibiotic-induced changes in gut bacteria can enhance immunity to Plasmodium. This effect is not universal but depends on baseline gut bacteria composition. These data demonstrate the dynamic communications that exist among gut bacteria, the gut-distal immune system, and control of Plasmodium infection.
