Identification of a T follicular helper cell subset that drives anaphylactic IgE

Abstract

Thirteen is the charm in anaphylaxis Immunoglobulin E (IgE) is a type of antibody associated with allergies and response to parasites such as worms. When high-affinity, allergen-specific IgE binds its target, it can cross-link receptors on mast cells that induce anaphylaxis. It remains unclear, however, how B cells are instructed to generate high-affinity IgE. Gowthaman et al. discovered a subset of T follicular helper cells (TFH13) that direct B cells to do just that. TFH13 cells are induced by allergens but not during parasite infection. Transgenic mice lacking these cells show impaired production of high-affinity, anaphylactic IgE. TFH13 cells, which are elevated in patients with food and aeroallergies, may be targeted in future antianaphylaxis therapies. Science, this issue p. eaaw6433 So-called TFH13 cells promote the production of high-affinity immunoglobulin E involved in allergic anaphylaxis. INTRODUCTION Cross-linking of high-affinity, allergen-specific immunoglobulin E (IgE) on mast cells results in anaphylaxis, a potentially life-threatening allergic reaction. The cellular mechanisms that induce B cells to produce high-affinity IgE to allergens remain poorly understood and likely differ from those that generate low-affinity IgE. T follicular helper (TFH) cells are the primary T cell subset responsible for directing the affinity, longevity, and isotype of antibodies produced by B cells; they have recently been found to be responsible for IgE responses as well. Yet the nature of the TFH cells that induce high-affinity IgE in allergic disease remains unclear. RATIONALE TFH cells guide B cell isotype switching via cytokine production. Although interleukin-4 (IL-4) has long been recognized to guide IgE switching, IL-4 is also a canonical TFH cell cytokine, expressed even when IgE is not made. This suggests that although IL-4 is necessary for high-affinity IgE, it is not sufficient, and additional TFH cell–derived signals are required. We hypothesized that a distinct but rare TFH cell population regulates the production of high-affinity IgE. To test this hypothesis, we used a model of dedicator of cytokinesis 8 (DOCK8) deficiency, which causes a monogenic form of allergy associated with aberrant production of IgE. Comparison of the TFH populations present in this model with wild-type mice immunized to food and aeroallergens enabled us to identify the nature of the T cell that induces anaphylactic IgE antibody production by B cells. RESULTS Regardless of immunization conditions, mice with T cell–specific Dock8 deficiency made allergen-reactive and anaphylactic IgE. This was associated with the presence of an unusual IL-4– and IL-13–producing TFH cell population in lymph nodes, which we call TFH13 cells. TFH13 cells demonstrated a distinctive transcription factor profile, including expression of BCL6 and GATA3. TFH13 cells were also induced in wild-type mice but only during immune responses when high-affinity IgE was made, including during food or aeroallergen sensitization. These cells were absent during immune responses lacking high-affinity IgE, including those induced by bacterial products or helminth infection. Patients who were allergic to peanut or aeroallergens also had elevated circulating TFH13 cells. Single-cell RNA sequencing analysis confirmed that TFH13 cells were distinct from related T helper 2 (TH2) or IL-4–expressing TFH2 cells. TFH13 cells could also be distinguished from IL-13–expressing effector TH2 cells by their subanatomical location in the germinal center. Conditional ablation of TFH13 cells or isolated loss of IL-13 in TFH cells resulted in impaired high-affinity, anaphylactic IgE responses to allergens. IgE and IgG1 germinal center B cells, but not naïve B cells, expressed the receptor for IL-13, suggesting that IL-13 may promote sequential switching of affinity-matured IgG1+ to high-affinity IgE+ B cells. CONCLUSION Our work describes a subset of T cells necessary for inducing anaphylactic IgE production to allergens. TFH13 cells and the molecular pathways operative in this distinctive population represent targets that could be leveraged diagnostically and therapeutically for allergies. Furthermore, the identification of TFH13 cells and the immune context in which they are induced solves the long-standing question of how, under rare circumstances, anaphylaxis-inducing IgE is produced by high-affinity B cells. Model of TFH cell–driven antibody production. Distinct TFH cell subsets dictate the outcome of antibody responses. TFH1 cells elicited to type 1 immunizations (bacterial or viral infections) do not induce IgE but promote pathogen neutralizing IgGs via production of IL-21 and interferon-γ (IFN-γ), with limited IL-4 production. During the type 2 immune responses to helminth infection, IL-4– and IL-21–producing TFH2 cells are induced, resulting in production of IgG and low-affinity IgE antibodies but not anaphylaxis. The IgE+ B cells in this case are derived from direct switching from low-affinity IgM+ B cells. In contrast, TFH13 cells are induced during allergic conditions and are necessary for the generation of high-affinity IgE, which results in anaphylactic responses. The high-affinity IgE+ B cells in this case are derived from sequentially switched and activated IgG1+ B cells. Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (TFH) cells direct the affinity and isotype of antibodies produced by B cells. Although TFH cell–derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13–producing TFH cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These “TFH13” cells have an unusual cytokine profile (IL-13hiIL-4hiIL-5hiIL-21lo) and coexpress the transcription factors BCL6 and GATA3. TFH13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking TFH13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.