AUTHOR=Montamat-Garcia Guillem , Bazon Murilo Luiz , Demczuk Agnieszka , Leonard Cathy , Ollert Markus 

TITLE=Tumor necrosis factor receptor 2 in allergen tolerance: a perspective view

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1613719

DOI=10.3389/fimmu.2025.1613719

ISSN=1664-3224

ABSTRACT=Central and peripheral tolerance are key to maintain immune homeostasis. Imbalance of these processes often leads to diseases such as allergy, cancer or autoimmune disorders. During the immune response to allergens, several regulatory immune cells play a role in the development of peripheral tolerance and maintenance of homeostasis by inhibiting the development of CD4+ type 2 helper T cells, impairing the production of pro-allergenic cytokines, reducing the activation of effector cells driving allergic inflammation and generating allergen-neutralizing antibodies. However, the precise mechanisms of how peripheral immune tolerance is effectively maintained in healthy people, but not in allergic patients are still not well understood. Immune checkpoints have recently been proposed as critical molecular pathways across diseases for understanding how the immune system maintains homeostasis in many pathologies such as cancer, type 1 diabetes, multiple sclerosis, Crohn’s disease and allergy, among others. Particularly in the context of allergy, in-depth studies on immune checkpoint pathways might lead to emerging therapeutic targets. Tumor necrosis factor receptor 2 (TNFR2) is a crucial protein involved in promotion, expansion and maintenance of immune tolerance, being suggested as a key target for the treatment of several immune-based diseases including allergy. Here, we review the involvement of TNFR2 in allergic inflammation and allergen tolerance, its structural properties, signaling pathways, and importance for immune tolerance as a common mechanism, with the focus on possible implications for novel immunomodulatory treatments of allergic diseases.