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 (M Phi s) constitute the major cellular subsets of APCs within the body; however, how and what types of resident M Phi s are involved in the regulation of immune homeostasis in the peripheral lymphoid tissues are poorly understood. Splenic red pulp M Phi (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(hi)Mac-1(low) M Phi s residing in the red pulp showed different expression patterns of surface markers compared with F4/80(+)Mac-1(hi) monocytes/M Phi s. Studies with purified cell populations demonstrated that F4/80(hi)Mac-1(low) M Phi s regulated CD4(+) T cell responses by producing soluble suppressive factors, including TGF-beta and IL-10. Moreover, F4/80(hi)Mac-1(low) M Phi s induced the differentiation of naive CD4(+) T cells into functional Foxp3(+) regulatory T cells. Additionally, we found that the differentiation of F4/80(hi)Mac-1(low) M Phi s was critically regulated by CSF-1, and in vitro-generated bone marrow-derived M Phi s 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(hi)Mac-1(low) M Phi s are a subpopulation of RPMs and regulate peripheral immune homeostasis. The Journal of Immunology, 2011, 186: 2229-2237.