Therapeutic blockade of CD3-mediated signaling ameliorates memory Th2-driven allergic asthma

Abstract Allergic asthma is an inflammatory disease of the lungs characterized by Type 2 helper T cell (Th2)-driven immune responses to inhaled allergens. Memory Th2 cells are a major driving force behind asthma, secreting cytokines like IL-4, IL-5, and IL-13 as well as persisting in the host long after allergen encounter. The selective removal of pre-existing memory Th2 cells could be a key process resulting in enhanced tolerance. One such method could involve targeting CD3 through the use of monoclonal anti-CD3 antibodies, which have been shown to successfully induce tolerance in animal models of autoimmune diseases and have also shown promise in clinical trials. We tested blocking CD3 complex signaling in a HDM model of allergic inflammation, to determine if we could induce airway tolerance. Importantly, pre-sensitized C57BL/6J mice displayed strongly ablated lung inflammation and Th2 responses when treated at the time of memory T cell reactivation with F(ab′)2 anti-CD3 antibody. This treatment was found to specifically inhibit HDM-specific CD4+ T cell proliferation and Th2 cytokine production. Interestingly, mice treated with anti-CD3 also showed an increased frequency of Treg cells, improving the Treg:Th2 cell ratio in favor of airway tolerance. Additionally, a significant reduction in airway inflammation and Th2 responses was maintained with therapeutic anti-CD3 antibody even when given several months later during a further memory T cell recall response to allergen. These data suggest that blocking signaling mediated by the CD3 complex could be employed to inhibit memory recall responses to complex allergens thus promoting airway tolerance.