Blocking the Migration of Circulatory T cells Mitigates the Accumulation of Allergen-induced Tissue-Resident Memory T cells

Abstract

Abstract Targeting lymphocyte egress from lymph nodes with S1PR agonists has been approved for multiple sclerosis and colitis, but their potential in asthma is unclear. Tissue-resident memory CD4 T cells (Trm) are thought to be a major contributor to asthma relapse but the role of circulatory T cells is not fully understood. We used a murine model of house dust mite allergen-driven asthma exacerbation and transient i.v. injection of antibody and the Trm markers CD44hi CD62Llo and CD69+ to distinguish lung-localized CD4 T cells from circulatory T cells. Trm were retained in lungs after the initial allergen encounter and expanded upon repeated allergen exposures. To determine the role of circulatory T cells, mice were given FTY720, a S1PR agonist. Blocking the primary migration of circulatory T cells alleviated the formation and accumulation of lung Trm. Even so, subsequent allergen challenges still resulted in strong Trm accumulation. This was blocked if FTY720 was also given during allergen re-exposure showing that new allergen-driven circulatory T cells formed this lung Trm pool at times well after the initial sensitization. In contrast, once lung Trm cells developed at high frequency, they no longer relied on circulatory T cells with their expansion and further survival of the Trm pool being unaffected by FTY720. Overall, this suggests that targeting circulatory T cells during allergen insults might be employed to inhibit the accumulation of lung Trm in individuals with recent-onset asthma and may promote long-lasting airway tolerance. However, in individuals that have had asthma for some time and developed a stable population of lung Trm, targeting circulatory T cells may be ineffective in reducing the pathogenic T cell pool that maintains disease