Protective role of tissue-resident Tregs in a murine model of beryllium-induced disease
Shaikh M. Atif, Douglas G. Mack, Allison K. Martin, Andrew P. Fontenot
Shaikh M. Atif, Douglas G. Mack, Allison K. Martin, Andrew P. Fontenot
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Research Article Pulmonology

Protective role of tissue-resident Tregs in a murine model of beryllium-induced disease

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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Figure 1

BeO exposure induces accumulation of FoxP3-expressing resident memory CD4+ T cells in the lung.

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BeO exposure induces accumulation of FoxP3-expressing resident memory CD...
HLA-DP2 Tg mice were exposed with 100 μg BeO, and lungs were harvested on day 21 and analyzed by flow cytometry. (A) Representative contour plot gated on lung CD4+ T cells show expression of CD44 and CD69. Three distinct CD4+ T cell subsets are enclosed in colored boxes: CD44–CD69– naive T cells (TN, green), CD44+CD69– Teffs (TE, blue), and CD44+CD69+ activated resident T cells (TR, black). Histogram shows CD62L expression on tissue-specific CD4+ naive T cells, Teffs, and activated resident T cells (same color coding as in A). Representative dot plot show CD103 and CD69 expression on CD4+ T cells. TR cells are broken down into resident memory (RM, purple box) and resident effector (RE, red box) T cells. (B) Frequency (left panel) and number (right panel) of CD4+ naive T cells, Teffs, and activated resident T cells in the lungs of BeO-exposed HLA-DP2 Tg mice. (C) Frequency (left panel) and number (right panel) of RE (CD103–CD69+) and RM (CD103+CD69+) CD4+ activated resident cells in the lungs of BeO-exposed HLA-DP2 Tg mice. (D) Representative contour plots showing expression of CD25 and FoxP3 staining on CD4+CD103+CD69+ RM T cells (purple) and CD4+CD103–CD69+ RE T cells (red). (E) Frequency (left panel) and number (right panel) of RM (CD103+CD69+) and RE (CD103–CD69+) CD4+ activated resident cells in the lungs of BeO-exposed HLA-DP2 Tg mice based on FoxP3 expression. Data (mean ± SEM) are representative of 3 independent experiments (3–5 mice per group). Student’s t test (C) and 1-way ANOVA (B and E) were used to test for differences. ***P < 0.001, **** P < 0.0001.