Antigen-Specific T Follicular Helper Cells Mediate Peanut Allergy in Mice

Background: Peanut (PN) allergy is a widespread and life-threatening medical problem. The prevalence of the disease has been increasing. However, our knowledge of the mechanisms involved in the development of peanut allergy is extremely limited. Several major questions remain including the route of peanut allergen sensitization and the cells and molecules involved in the sensitization process. The goal of this project was to use mouse models and fill these major gaps in our knowledge.

Methods: We administered peanut (PN) flour intranasally (i.n.) to BALB/c (once/week) and C57Bl/6 (twice/week) for 4-weeks; no adjuvants were used. Mice were then challenged by intraperitoneal (i.p.) injection of PN extract. Development of anaphylactic response was monitored by rectal temperature and clinical symptom scores. Development of PN-specific Th2 cells and T follicular helper (Tfh) cells was analyzed by using the IL-4-IRES-eGFP (4get) reporter mouse. Role of Tfh cells were examined by using CD4-cre+ Bcl6^fl/flmice, which are deficient in Tfh-specific transcription factor Bcl6.    

Results: Intranasal exposure of mice to peanut flour sensitized naïve BALB/c and C57Bl/6 mice without any additional adjuvants, and these mice developed PN-specific IgE and IgG1 antibodies. When mice were challenged i.p. with PN extract, they developed anaphylactic responses, including lower body temperature and several clinical signs (e.g. rubbing, labored breathing, slowed motility) consistent with anaphylaxis.  When exposed to PN flour, 4get mice developed Tfh cells (CD4+ CXCR5+ ST2- IL-4eGPP+), but few Th2 cells (CD4+ CXCR5- ST2+ IL-4eGFP+). Tfh-deficient mice failed to produce PN-specific IgE and IgG antibodies and they were protected from developing anaphylaxis upon PN challenge.

Conclusion: These findings suggest that allergen sensitization to PN can occur by airborne exposure. Furthermore, Tfh cells, but unlikely Th2 cells, play a major role in development of IgE antibodies and clinical outcomes. Significance of Tfh cells as compared to conventional Th2 cells in various allergic diseases need to be evaluated in future.