Sunday, May 11, 2025
5/11/2025
TFH cell programming for IgE responses - Allergic disease greatly impacts the quality of life in the United States and costs billions of dollars annually on health care and lost productivity. IgE is the primary mediator for the immediate hypersensitivity phase of the allergic response and can also drive life-threatening anaphylaxis. Allergen-specific IgE is produced in germinal center (GC) reactions and requires help from IL-4-secreting T follicular helper (TFH) cells. TFH cells localize to the GC, where they promote B cell clonal expansion and antibody affinity maturation. A major unresolved question is what factors control the development of TFH cells that promote IgE responses. High affinity IgE antibodies are formed in allergic responses which involve the development of IL-4- expressing TH2 cells and IL-4-expressing TFH cells (sometimes referred to as TFH2 cells). However, the developmental connection between TH2 cells generated in allergic responses and TFH2 cells is unresolved. Additionally, IL-4-expressing TFH cells can develop without the production of significant IgE responses. In a recent study, using a food allergy priming model in mice, we characterized TFH cells that developed under two different methods of priming using the same allergen and adjuvant, but varying in the timing of the priming. We analyzed the TFH cells that developed under these two conditions and identified significant differences in gene expression. In both priming conditions, IL-4-expressing TFH cells developed, but IgE responses only developed in only one priming condition. We termed the TFH cells that promote IgE in this system as TFH-IgE cells, to distinguish them from TFH2 cells. Our goal in this application is to define the requirements for TFH-IgE cell development. We have found that Anxa1, a regulatory gene which is a known inhibitor of TH2 and IgE responses, is strongly down-regulated in TFH-IgE cells compared to TFH2 cells. The role of Anxa1 in TFH cell function has not been previously explored, however new findings reveal that Anxa1 expression is down-regulated by IL-4 signaling in activated CD4 T cells. We therefore hypothesize that Anxa1 is a signal modulating protein that inhibits the development of TFH-IgE cells, and that, in contrast to TFH2 cells, TFH-IgE cells are generated by IL-4-Stat6 signals which critically down-regulate Anxa1 expression to allow full TFH-IgE differentiation (characterized by increased IL-4, CD40L; decreased Fgl2 and Entpd1).
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