Protective role of tissue-resident regulatory T cells in a murine model of beryllium-induced disease

CD4⁺ T cells drive the immunopathogenesis of chronic beryllium disease (CBD), and their recruitment to the lung heralds the onset of granulomatous inflammation. We have shown that regulatory CD4⁺ T cells (Tregs) control granuloma formation in an HLA-DP2 transgenic (Tg) model of CBD. In these mice, Be oxide (BeO) exposure resulted in the accumulation of three distinct CD4⁺ T cell subsets in the lung with the majority of tissue-resident memory cells expressing FoxP3. The amount of Be regulated the number of total and antigen-specific CD4⁺ T cells and Tregs in the lungs of HLA-DP2 Tg mice. Depletion of Tregs increased the number of IFN-γ-producing CD4⁺ T cells and enhanced lung injury while mice treated with IL2/αIL-2 complexes had increased Tregs and reduced inflammation and Be-responsive T cells in the lung. BeO-experienced resident Tregs suppressed anti-CD3-induced proliferation of CD4⁺ T cells in a contact-dependent manner. CLTLA-4 and ICOS blockade as well as addition of LPS to BeO-exposed mice increased the Teff/Treg ratio and enhanced lung injury. Collectively, these data show that the protective role of tissue-resident Tregs is dependent on quantity of Be exposure and is overcome by blocking immune regulatory molecules or additional environmental insults.