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 IgG₄. However, the specific T-cell response that leads to IgG₄ induction during chronic allergen exposure remains poorly understood.

We sought to evaluate the relationship between cat allergen–specific T-cell frequency, cat allergen–specific IgE and IgG₄ titers, and clinical status in adults with cat allergy with and without cat ownership and the cellular mechanism by which IgG₄ is produced.

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.

In allergic subjects without cat ownership, the frequency of cat allergen (Fel d 1 and Fel d 4)–specific T_H2 (sT_H2) 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_H2 cells, which correlates with higher IgG₄ levels and low sensitization. B cells from allergic, but not nonallergic subjects, are able to produce IgG₄ after cognate interactions with sT_H2 clones and Fel d 1 peptide or the Fel d 1 recombinant protein.

These experiments suggest that (1) allergen-experienced B cells with the capacity to produce IgG₄ are present in allergic subjects and (2) cat allergen exposure induces an IgG₄ response in a T_H2 cell–dependent manner. Thus IgG₄ accumulation could be mediated by chronic activation of the T_H2 response, which in turn drives desensitization.