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 (T_FH) 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 T_FH cells that induce high-affinity IgE in allergic disease remains unclear.

T_FH 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 T_FH 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 T_FH cell–derived signals are required. We hypothesized that a distinct but rare T_FH 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 T_FH 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.

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 T_FH cell population in lymph nodes, which we call T_FH13 cells. T_FH13 cells demonstrated a distinctive transcription factor profile, including expression of BCL6 and GATA3. T_FH13 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 T_FH13 cells. Single-cell RNA sequencing analysis confirmed that T_FH13 cells were distinct from related T helper 2 (T_H2) or IL-4–expressing T_FH2 cells. T_FH13 cells could also be distinguished from IL-13–expressing effector T_H2 cells by their subanatomical location in the germinal center. Conditional ablation of T_FH13 cells or isolated loss of IL-13 in T_FH 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.

Our work describes a subset of T cells necessary for inducing anaphylactic IgE production to allergens. T_FH13 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 T_FH13 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.

Distinct T_FH cell subsets dictate the outcome of antibody responses. T_FH1 cells elicited to type 1 immunizations (bacterial or viral infections) do not induce IgE but …