1. Allergens (+ T H2 adjuvants?) T H2 dominancy Allergen exposure with microbial components Early in life Later in life T H1 dominancy Cross inhibition Atopy Non atopy TNTN T H2 T H1 TNTN TNTN TNTN TNTN TNTN TNTN T H2 TNTN T H1 TNTN Orihara K, et al. Fig.1

2. T REG T H2 IL-4, IL-13, IL-5 Contact inhibition IL-10, TGF-  IL-12, IFN-  IL-17, IL-6 Anti-viruses Anti-bacteria Anti-parasite Orihara K, et al. Fig.2 T H1 T H17 Plant Antigens, Parasites, Molds, Viruses and Bacteria

3. rT H2 IL-17 IL-4 IL-13 IL-5 TNF-  Allergic diseases IgE Eosinophils iT H2 Orihara K, et al. Fig.3a IFN-  IFN-  T H1 T H17 T REG Viruses Mast cell activation (+)

4. iT H2 IL-4 IL-13 IL-5 IL-10 IgE Eosinophils Asymptomatic atopy rT H2 T REG aT REG Orihara K, et al. Fig.3b IFN-  T H17 T H1 IFN-  IL-10 Viruses Mast cell activation (  )

5. T H2 dominancy=atopy T H1 dominancy T H2 T H1 T H2 TNTN T H1 TNTN Allergic diseases iT H2 T H17 iT H2 T H17 iT H2 T H17 Healthy T REG T H1 T REG T H1 T H17 T H1 T H17 Autoimmune diseases T REG rT H2 T REG rT H2 Asymptomatic atopy IL-17, TSLP, IL-6 Microbial components Pure Allergens Orihara K, et al. Fig.4 TGF- , IL-10