Naive T cells sense the cysteine protease allergen papain through protease-activated receptor 2 and propel TH2 immunity

Background: Sensitization to protease allergens, such as papain, or helminth infection is associated with basophil recruitment to draining lymph nodes (LNs). Basophils have the capacity to present antigen to naive T cells and promote T(H)2 differentiation directly or indirectly through IL-4 production. Objective: We studied how papain induces basophil migration to LNs and the contribution of various leukocytes to papain-induced immune responses. Methods: We immunized mice in the footpad with papain and studied leukocyte recruitment and inflammatory cytokine and chemokine production in the draining popliteal LNs. Results: Papain directly activated naive T cells through protease-activated receptor (PAR) 2 to initiate a chemokine/cytokine program that includes CCL17, CCL22, and IL-4. Papain-triggered innate immune responses were dependent on both CD4 T cells and PAR2 and were strongly reduced in the absence of CCR4, the primary receptor for CCL17/CCL22. Conclusion: These results elucidate a novel innate allergen-recognition pathway mediated by naive T cells through PAR2, which provide an immediate source of chemokines and IL-4 upstream of basophils and antigen-restricted T(H)2 differentiation. PAR2 antagonism might thus hold promise for the treatment of allergic disease. (J Allergy Clin Immunol 2012;129:1377-86.)