Inhibition of allergen-specific tissue resident memory Th2 cells through blockade of CD3-mediated signaling ameliorates allergic lung inflammation

Abstract

Abstract Allergic asthma remains a major public health concern, with more than 26 million Americans suffering from the disease. The secretion of cytokines such as IL-4, IL-5, and IL-13 and their ability to persist in the host long after the primary allergen encounter are a reason memory Th2 cells are a major driving force behind allergic asthma morbidity. The selective removal of pre-existing memory Th2 cells could be a key therapeutic venture to enhance tolerance. One such method could involve targeting CD3 through the use of inhibitory anti-CD3 antibodies which successfully induced tolerance in animal models of autoimmune diseases and also show promise in clinical trials. To determine if we could induce airway tolerance, we tested blocking CD3 complex signaling in a HDM model of allergic inflammation. 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 inhibit HDM-specific CD4+ T cell proliferation and Th2 cytokine production. Interestingly, while mice treated with anti-CD3 also showed an increased frequency of Treg cells, protection to allergic inflammation was maintained even after Treg depletion. Anti-CD3 treatment was found to specifically inhibit eosinophilic lung inflammation driven by allergen-specific lung tissue resident memory (Trm) Th2 cells as determined by treatment of mice with fingolimod (FTY720), which prevents the recruitment and contribution of circulating memory T cells to the allergic response. These data suggest that blocking CD3 complex signaling could be employed to inhibit Trm recall responses to complex allergens thus promoting airway tolerance.