Anti‐CD3 inhibits circulatory and tissue‐resident memory CD4 T cells that drive asthma exacerbations in mice

Background Exacerbations of asthma are thought to be strongly dependent on reactivation of allergen‐induced lung tissue‐resident and circulatory memory CD4 T cells. Strategies that broadly inhibit multiple T cell populations might then be useful to limit asthma. Accordingly, we tested whether targeting CD3 during exposure to inhaled allergen could prevent the accumulation of lung‐localized effector memory CD4 T cells and block exacerbations of asthmatic inflammation. Methods House dust mite‐sensitized and repetitively challenged BL/6 mice were transiently treated therapeutically with F(ab′)2 anti‐CD3ε and memory T cell responses and lung inflammation were assessed. PBMCs from HDM‐allergic donors were examined for the effect of anti‐CD3 on expansion of allergen‐reactive T cells. Results Allergen‐sensitized mice undergoing exacerbations of asthma were protected from lung inflammation by transient therapeutic treatment with F(ab′)2 anti‐CD3. Regardless of whether sensitized mice underwent a secondary or tertiary recall response to inhaled allergen, anti‐CD3 inhibited all phenotypes of effector memory CD4 T cells in the lung tissue and lung vasculature by 80%–90%, including those derived from tissue‐resident and circulatory memory T cells. This did not depend on Treg cells suggesting it was primarily a blocking effect on memory T cell signaling. Correspondingly, anti‐CD3 also strongly inhibited proliferation of human allergen‐reactive memory CD4 T cells from allergic individuals. In contrast, the number of surviving tissue‐resident memory CD4 T cells that were maintained in the lungs at later times was not robustly reduced by anti‐CD3. Conclusion Anti‐CD3 F(ab′)2 administration at the time of allergen exposure represents a viable strategy for limiting the immediate activity of allergen‐responding memory T cells and asthma exacerbations. Therapeutic treatment with anti‐CD3 F(ab′)2 fragments inhibits exacerbations of allergen‐driven asthmatic lung inflammation in mice. Anti‐CD3 limits the expansion of tissue‐resident and circulatory memory CD4 T cells. Anti‐CD3 ameliorates proliferation of human HDM‐reactive memory CD4 T cells. Abbreviations: BALF, bronchoalveolar lavage fluid; EOS, eosinophil; HDM, house dust mite; NEU, neutrophil; PAS, periodic acid‐Schiff; TCR, T‐cell receptor