Regulation of germinal centers by thymic stromal lymphopoietin in mice and humans

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PROJECT SUMMARY IgE antibodies to environmental proteins are detected in up to 40% of the worldwide population, and the prevalence of allergic disease continues to rise in industrialized nations. Although several therapies can mitigate antibody-driven anaphylaxis or block antibody effector functions, high mortality rates persist without a curative treatment, and the mechanisms that control allergen-specific antibody production are still poorly understood. Previous work from our group and others showed that Thymic Stromal Lymphopoietin (TSLP) is required for the development allergic disease, and we recently discovered that TSLP also plays an additional role in controlling IgE and IgG1 antibody production in germinal centers (GCs). GC B cells and T follicular helper cells upregulate the expression of surface TSLP receptor (TSLPR) as they enter into the GC microenvironment, and TSLPR- deficient mice produce significantly lower titers of antigen-specific IgG1 and IgE upon immunization. When CD4+ T cells specifically lack TSLPR expression (CD4creTSLPRF/F), immunized mice develop similar frequencies of antigen-specific germinal centers, but lower numbers of IgG1-producing B cells with high-affinity for antigen, suggesting that TSLPR expression on T cells may be required for affinity maturation in the germinal center. Therefore, we hypothesize that Tfh cells and germinal center B cells differentially regulate germinal center activity by two distinct mechanisms. Here, we will ask how TSLPR signaling in each of these cell populations independently regulate the production of IgE/IgG1 antibodies in mouse models, and we will perform follow-up experiments to confirm that TLSP-blocking therapy can reduce the number of allergen-specific plasma cells and Tfh cells in patients with cat allergies. Overall, our research into the connection between TSLP receptor signaling and allergen-specific germinal center responses could build a foundation to establish novel therapeutics to treat or prevent the onset of allergic disease.