Control of regulatory T cells and airway tolerance by lung macrophages and dendritic cells

Abstract

Airway tolerance, a state of immunological surveillance, suppresses the development of lung inflammatory disorders that are driven by various pathological effector cells of the immune system. Tolerance in the lung to inhaled antigens is primarily mediated by regulatory T cells (Treg cells) that can inhibit effector T cells via a myriad of mechanisms. Accumulating evidence suggests that regulatory antigen-presenting cells are critical for generating Treg cells and/or maintaining the suppressive environment in the lung. This review focuses on the control of airway tolerance by Treg cells and the role of regulatory lung tissue and alveolar macrophages, and lung and lymph node dendritic cells, in contributing to airway tolerance that is associated with suppression of allergic asthmatic disease.

Keywords: airway tolerance; dendritic cells; lung; macrophages; regulatory T cells.

Figure 1.

Schematic depicting possible interactions between T cells, macrophages, and dendritic cells that result in the formation of inducible Treg cells (iTreg cells) in the lung and lung-draining lymph nodes (LNs). For simplicity, alveolar and tissue macrophages have been grouped together, but it is still to be determined whether they exhibit divergent activities. Tolerance may be afforded by both early and late interactions. Early interactions would involve intrinsic activities of antigen-presenting cells (APCs) in the steady state when soluble pure protein antigen is taken up in the lung. Two primary scenarios are possible. Left: Regulatory macrophages (MØreg) in the lung that constitutively make transforming growth factor (TGF)-β and retinoic acid (RA) directly present antigen to naive CD4⁺ T cells (green), resulting in the formation of forkhead box P3–positive (Foxp3⁺) or latency-associated peptide–positive (LAP⁺) iTreg cells (blue). These iTreg cells migrate to the lymph nodes and encounter antigen presented on immature conventional DCs (cDCs), which results in their expansion and movement back to the lung. Right: Immature cDCs in the lung take up antigen and migrate to the lymph nodes, where they activate naive CD4⁺ T cells. These undifferentiated cells expand in numbers, move back to the lung, and then are stimulated by antigen presented on lung MØreg. This results in differentiation into Foxp3⁺ or LAP⁺ iTreg cells driven by TGF-β and RA. Regulatory plasmacytoid DCs (pDCreg cells) in the lymph nodes may also aid these processes. Some T cells are additionally induced to become anergic by interaction with MØreg and immature cDCs, or undergo deletion. At a later time, likely under the influence of low-level signals from antigen and innate stimuli such as LPS, immature cDCs differentiate into regulatory cells (cDCreg) in the lymph nodes and gain the capacity to make TGF-β, RA, and/or IL-10. Similarly, lung MØreg also gain the capacity to make IL-10. Together, this may either maintain the existing population of iTreg cells, or promote the generation of more iTreg cells that could be Foxp3⁺ or IL-10⁺.