Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy

Allergic diseases are characterized by overactive type 2 immune responses to allergens and immunoglobulin E (IgE)-mediated hypersensitivity. Emerging evidence suggests that follicular helper T (T-FH) cells, rather than type 2 T-helper (T(H)2) cells, play a crucial role in controlling IgE production. However, follicular regulatory T (T-FR) cells, a specialized subset of regulatory T (T-REG) cells resident in B-cell follicles, restricts T-FH cell-mediated help in extrafollicular antibody production, germinal center (GC) formation, immunoglobulin affinity maturation, and long-lived, high-affinity plasma and memory B-cell differentiation. In mouse models of allergic asthma and food allergy, CXCR5(+) T-FH cells, not CXCR5(-) conventional T(H)2 cells, are needed to support IgE production, otherwise exacerbated by CXCR5(+) T-FR cell deletion. Upregulation of T-FH cell activities, including a skewing toward type 2 T-FH (T(FH)2) and IL-13 producing T-FH (T(FH)13) phenotypes, and defects in T-FR cells have been identified in patients with allergic diseases. Allergen immunotherapy (AIT) reinstates the balance between T-FH and T-FR cells in patients with allergic diseases, resulting in clinical benefits. Collectively, further understanding of T-FH and T-FR cells and their role in the immunopathogenesis of allergic diseases creates opportunities to develop novel therapeutic approaches.