Chronic cat allergen exposure induces a TH2 cell-dependent IgG4 response related to low sensitization

Background: In human subjects, allergen tolerance has been observed after high-dose allergen exposure or after completed allergen immunotherapy, which is related to the accumulation of anti-inflammatory IgG(4). However, the specific T-cell response that leads to IgG(4) induction during chronic allergen exposure remains poorly understood. Objective: We sought to evaluate the relationship between cat allergen-specific T-cell frequency, cat allergen-specific IgE and IgG(4) titers, and clinical status in adults with cat allergy with and without cat ownership and the cellular mechanism by which IgG(4) is produced. Methods: Fel d 1-, Fel d 4-, Fel d 7-, and Fel d 8-specific T-cell responses were characterized by CD154 expression after antigen stimulation. Results: In allergic subjects without cat ownership, the frequency of cat allergen (Fel d 1 and Fel d 4)-specific T(H)2 (sT(H)2) cells correlates with higher IgE levels and is linked to asthma. Paradoxically, we observed that subjects with cat allergy and chronic cat exposure maintain a high frequency of sT(H)2 cells, which correlates with higher IgG(4) levels and low sensitization. B cells from allergic, but not nonallergic subjects, are able to produce IgG(4) after cognate interactions with sT(H)2 clones and Fel d 1 peptide or the Fel d 1 recombinant protein. Conclusion: These experiments suggest that (1) allergen-experienced B cells with the capacity to produce IgG(4) are present in allergic subjects and (2) cat allergen exposure induces an IgG(4) response in a T(H)2 cell-dependent manner. Thus IgG(4) accumulation could be mediated by chronic activation of the T(H)2 response, which in turn drives desensitization.