Affiliation:
1. Center for Autoimmunity and Inflammation La Jolla Institute for Immunology La Jolla California USA
2. Center for Infectious Disease and Vaccine Research La Jolla Institute for Immunology La Jolla California USA
3. Department of Medicine University of California San Diego La Jolla California USA
Abstract
AbstractBackgroundExacerbations 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.MethodsHouse 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.ResultsAllergen‐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.ConclusionAnti‐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.
Subject
Immunology,Immunology and Allergy