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Abstract
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 CD4+ Tregs control granuloma formation in an HLA-DP2 Tg model of CBD. In these mice, beryllium oxide (BeO) exposure resulted in the accumulation of 3 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 IL-2/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. CTLA-4 and ICOS blockade, as well as the addition of LPS to BeO-exposed mice, increased the effector T cell (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.
Authors
Shaikh M. Atif, Douglas G. Mack, Allison K. Martin, Andrew P. Fontenot
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