IL-4-producing B cells regulate T helper cell dichotomy in type 1- and type 2-controlled diseases

Area of Science:

• Immunology
• Parasitology
• Cell Biology

Background:

• Interleukin-4 (IL-4)-induced T helper (Th) 2 cells differentially impact parasitic infections, promoting susceptibility to Leishmania major while conferring immunity to Schistosoma mansoni.
• B cells are key players in immune responses, but their specific role in regulating Th2 responses in parasitic infections requires further elucidation.
• IL-4 receptor alpha (IL-4Rα) signaling is crucial for Th2 cell differentiation and function.

Purpose of the Study:

• To investigate the role of IL-4 receptor alpha (IL-4Rα) signaling on B cells in regulating immune responses to Leishmania major and Schistosoma mansoni.
• To determine how modulating IL-4Rα signaling on B cells affects T helper cell dichotomy and disease outcomes in these parasitic infections.

Main Methods:

• Generation of B cell-specific IL-4Rα-deficient mice (mb1creIL-4Rα-/lox) in BALB/c background.
• Adoptive reconstitution and mixed bone-marrow chimera studies in B cell-deficient (µMT) mice.
• Assessment of immune responses, including T helper cell polarization and pathology, following infection with Leishmania major and Schistosoma mansoni.

Main Results:

• Abrogation of IL-4Rα signaling on B cells in BALB/c mice shifted the immune response from non-healer to healer in Leishmania major infection, characterized by reduced Th2 response and absence of pathology.
• B cell-derived IL-4 and IL-4Rα signaling are essential for the induction of the susceptible Th2 phenotype in Leishmania major infection.
• Absence of IL-4Rα signaling on B cells exacerbated mortality and pathology in Schistosoma mansoni-infected mice due to a diminished Th2 response.
• IL-4Rα-responsive B cells exhibited increased IL-4 production early in both infections.

Conclusions:

• B cells are critical regulators of early T helper dichotomy, directing responses towards Th2 immunity.
• IL-4-producing and IL-4Rα-responsive B cells play a detrimental role in cutaneous leishmaniasis but a beneficial role in acute schistosomiasis.
• Targeting IL-4Rα signaling on B cells represents a potential therapeutic strategy for modulating immune responses in parasitic infections.