CD11b+Gr-1dim Tolerogenic Dendritic Cell-Like Cells Are Expanded in Interstitial Lung Disease in SKG Mice

Abstract

Objective: SKG mice develop interstitial lung disease (ILD) resembling rheumatoid arthritis-associated ILD in humans. The aim of this study was to clarify the mechanism underlying the lung pathology by analyzing lung-infiltrating cells in SKG mice with ILD.

Methods: We assessed the severity of zymosan A (ZyA)-induced ILD in SKG mice histologically, and we examined lung-infiltrating cells by flow cytometry. Total lung cells and isolated monocytic myeloid-derived suppressor cells (MDSCs) were cultured in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. The proliferation of 5,6-carboxyfluorescein diacetate N-succinimidyl ester-labeled naive T cells cocultured with isolated CD11b+Gr-1^dim cells and MDSCs was evaluated by flow cytometry. CD11b+Gr-1^dim cells were adoptively transferred to ZyA-treated SKG mice.

Results: MDSCs, Th17 cells, and group 1 and 3 innate lymphoid cells (ILC1s and ILC3s) were increased in the lungs; the proportion of these cells varied with ILD severity. In this process, we found that a unique cell population, CD11b+Gr-1^dim cells, was expanded in the severely inflamed lungs. Approximately half of the CD11b+Gr-1^dim cells expressed CD11c. CD11b+Gr-1^dim cells were induced from monocytic MDSCs with GM-CSF in vitro and were considered tolerogenic because they suppressed T cell proliferation. These CD11b+Gr-1^dim cells have never been described previously, and we termed them CD11b+Gr-1^dim tolerogenic dendritic cell (DC)-like cells. Th17 cells, ILC1s, and ILC3s in the inflamed lung produced GM-CSF, which may have expanded CD11b+Gr-1^dim tolerogenic DC-like cells in vivo. Furthermore, adoptive transfer of CD11b+Gr-1^dim tolerogenic DC-like cells significantly suppressed progression of ILD in SKG mice.

Conclusion: We identified unique suppressive myeloid cells that were differentiated from monocytic MDSCs in SKG mice with ILD, and we termed them CD11b+Gr-1^dim tolerogenic DC-like cells.