CSF-1-dependent red pulp macrophages regulate CD4 T cell responses

The balance between immune activation and suppression must be regulated to maintain immune homeostasis. Tissue macrophages (MΦs) constitute the major cellular subsets of APCs within the body; however, how and what types of resident MΦs are involved in the regulation of immune homeostasis in the peripheral lymphoid tissues are poorly understood. Splenic red pulp MΦ (RPMs) remove self-Ags, such as blood-borne particulates and aged erythrocytes, from the blood. Although many scattered T cells exist in the red pulp of the spleen, little attention has been given to how RPMs prevent harmful T cell immune responses against self-Ags. In this study, we found that murine splenic F4/80^hiMac-1^low MΦs residing in the red pulp showed different expression patterns of surface markers compared with F4/80 ⁺Mac-1^hi monocytes/MΦs. Studies with purified cell populations demonstrated that F4/80^hiMac-1^low MΦs regulated CD4⁺ T cell responses by producing soluble suppressive factors, including TGF-β and IL-10. Moreover, F4/80^hiMac-1 ^low MFs induced the differentiation of naive CD4⁺ T cells into functional Foxp3⁺ regulatory T cells. Additionally, we found that the differentiation of F4/80^hiMac-1^low MΦs was critically regulated by CSF-1, and in vitro-generated bone marrow-derived MΦs induced by CSF-1 suppressed CD4⁺ T cell responses and induced the generation of Foxp3⁺ regulatory T cells in vivo. These results suggested that splenic CSF-1-dependent F4/80^hiMac-1^low MΦs are a subpopulation of RPMs and regulate peripheral immune homeostasis.