A mechanism for the initiation of allergen-induced T helper type 2 responses

Caroline L Sokol, Gregory M Barton, Andrew G Farr & Ruslan Medzhitov

2008. Nature Immunol. 9(3), 310 - 318

Speaker: 廖宏明                                           Time: 15:00~16:00, Mar. 26, 2008

Commentator: 葉怡玲 老師                        Place: Room 601

Abstract:

T_H2 responses is associated with parasitic and atopic disease¹, but little is known about the recognition mechanisms of innate immune in the initiation of T_H2 responses. T_H2-regulated immune responses are induced after helminth or simple protein allergens infection and are characterized by activation of eosinophils, mast cells and mucosal epithelial cells and production of IgE². Using papain, a cysteine protease, to immunize mice, authors found the production of IgE and IgG1 was stimulated. Immunizing with papain will activates DC migration and maturation in vivo, but in vitrotreatment of DCs with papain did not induce DC maturation. So the authors hypothesized that there are other T_H2-inducing signals expressed together with IL-4. Using ‘4get’ mice, in which cells activate the gene encoding IL-4 (Il4) can be visualized by eGFP ‘knocked into’ the Il4 locus (IL-4-eGFP), they found an accumulation of IL-4-eGFP⁺ T_H2 cells in the draining lymph nodes. The IL-4-eGFP⁺ cells in the draining lymph node, were basophils. Depleting basophils in mice abolished the T_H2 responses induced by papain. IgE crosslinking or using papain to activate basophils, induced production of IL-4, IL-6 , TNF, Thymic stromal lymphopoietin (TSLP), and other T_H2 cytokines by basophils in vitro. TSLP is an IL-7-like cytokine involvement in lymphocyte development and allergic responses³. Using a TSLP-neutralizing monoclonal antibody to neutralize TSLP in vivo led to considerable inhibition of T_H2 differentiation without affecting DC maturation and migration. Activation of naïve T cell in the presence of TSLP led to the production of T_H2-specific cytokines and the transcription factor GATA-3, which is essential for T_H2 differentiation. Taken together, these findings support a model for the innate initiation of T_H2 responses based on the sensing of protease activity of allergens and possibly helminths by basophils.

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