Lung Interstitial Macrophages Can Present Soluble Antigens and Induce Foxp3⁺ Regulatory T Cells

Lung macrophages constitute a sophisticated surveillance and defense system that contributes to tissue homeostasis and host defense and allows the host to cope with the myriad of insults and antigens to which the lung mucosa is exposed. As opposed to alveolar macrophages, lung interstitial macrophages (IMs) express high levels of Type 2 major histocompatibility complex (MHC-II), a hallmark of antigen-presenting cells. Here, we showed that lung IMs, like dendritic cells, possess the machinery to present soluble antigens in an MHC-II-restricted way. Using ex vivo ovalbumin (OVA)-specific T cell proliferation assays, we found that OVA-pulsed IMs could trigger OVA-specific CD4⁺ T cell proliferation and Foxp3 expression through MHC-II-, IL-10-, and transforming growth factor β-dependent mechanisms. Moreover, we showed that IMs efficiently captured locally instilled antigens in vivo, did not migrate to the draining lymph nodes, and enhanced local interactions with CD4⁺ T cells in a model of OVA-induced allergic asthma. These results support that IMs can present antigens to CD4⁺ T cells and trigger regulatory T cells, which might attenuate lung immune responses and have functional consequences for lung immunity and T cell-mediated disorders.