The goals of this review are to address the effects of chronic high-dose allergen exposure on the allergen-specific CD4(+) T-cell subset during allergen-specific immunotherapy (AIT), as well as recent discoveries suggesting new pathways for desensitization and tolerance induction during AIT. New tools for direct molecular and cellular investigation have now made it possible to compare the activities and phenotypes of allergen-specific T lymphocytes at the single-cell level in the context of illness and therapeutic intervention. AIT has been shown in recent investigations to restore tolerance by transiently activating interleukin (IL)-10 generating T cells followed by selective deletion of allergen-specific TH2 cells.

With antigen-specific TH2 cells at the heart of the allergic process in atopic people, the length and amount of antigen exposure may be the driving force behind current AIT protocols. Autocrine IL-10 production to prevent excessive TH2 cell effector responses, T-cell fatigue, and selective proallergic TH2 cell deletion may all be mechanisms controlling allergen-specific CD4(+) T-cell responses, allowing for concurrent downregulating T-cell responses to arise. AIT administered in the context of immune modifying methods capable of inducing a counter-regulatory immune response may result in better AIT with long-term therapeutic benefit.