Protective Role of Tissue-Resident Regulatory T Cells in a Murine Model of Beryllium-Induced Disease

Abstract

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 regulatory CD4+ T cells (Tregs) control granuloma formation in an HLA-DP2 transgenic (Tg) model of CBD. In Be oxide (BeO)-exposed HLA-DP2 Tg mice, the majority of tissue-resident memory cells (CD44+CD69+CD103+) expressed FoxP3 while resident effector cells (CD44+CD69+CD103−) lacked FoxP3. Increased numbers of tissue-resident effector and regulatory CD4+ T cells accumulated in the lung following BeO exposure. 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. 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 time and quantity of Be exposure and is overcome by additional environmental insults. Finally, our findings suggest a potential therapeutic role of Treg expansion as an adjunctive therapeutic option in granulomatous lung disease. This work was supported by the following NIH grants: ES025534, HL062410, HL102245, and HL152756 (to Andrew P. Fontenot).