The role of T follicular helper cells in induction and affinity maturation of IgE in immune responses to venom

• Applicant: Dr. Magdalena Kraft
• Subject Area: Clinical Immunology and Allergology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 464546188

Immediate-type allergic diseases are an emerging health challenge, affecting one‐third of the population in high gross domestic product countries. These diseases are characterized by the presence of immunoglobulin E (IgE), which is pivotal for specificity, rapid onset, and long‐lasting memory of allergic immune response. Nevertheless, IgE has also an important protective function against venom toxins. Envenomation due to bites of venomous animals account for more than 100,000 deaths every year and IgE mediated protection against venom might play a crucial role in enhancing survival. On the other hand, venom-specific IgE (sIgE) might elicit severe anaphylaxis in certain individuals that can be more life‐threatening than the envenomation itself. The affinity of venom sIgE and the mechanism of its induction were rarely investigated. In general, high-affinity immunoglobulins are induced by the process of the germinal center reaction for which an interaction between B cells and T follicular helper (Tfh) cells is essential. It has been recently revealed that a distinct population of GATA3-expressing and interleukin (IL) 13-producing Tfh13 cells directs the B cells toward the production of high-affinity IgE. This specialized subset of Th cells was not required for the production of total IgE and mice that were deficient in these cells showed normal titers of total IgE and sIgE upon immunization. However, Tfh13 cells were indispensable for the production of high-affinity, anaphylactic IgE to aeroallergens (but not the parasite N. brasiliensis). Currently, there are no data available on Tfh(13) cells in venom allergy. Here, we aim to investigate the role of Tfh and, in particular, Tfh13 cells in the induction of IgE against venom. For this purpose, we will use an animal venom-IgE immune response model. This will allow us to characterize the induced populations of T and B cells. Furthermore, the role of different T-cell subsets and cytokines will be investigated using different knockout mice. Additionally, the examination of sIgE and allergen-specific Tfh cells from the blood of patients who are allergic to venom and those who are sensitized but not allergic to venom will help us to investigate the affinity of sIgE to venom and the role of different Tfh-cell subsets in its induction in humans. The knowledge gained through this project may not only help to understand the development of venom sIgE and venom allergy but also provide insights into the basic mechanisms of IgE induction relevant for the development of other IgE-mediated diseases.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Dr. Stephanie Eisenbarth