title: Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth.
abstract: Regulatory T cells (T reg cells) are characterized by the expression of the forkhead lineage-specific transcription factor Foxp3, and their main function is to suppress T cells. While evaluating T reg cells, we identified a population of Foxp3-positive cells that were CD11b(+)F4/80(+)CD68(+), indicating macrophage origin. These cells were observed in spleen, lymph nodes, bone marrow, thymus, liver, and other tissues of naive animals. To characterize this subpopulation of macrophages, we devised a strategy to purify CD11b(+)F4/80(+)Foxp3(+) macrophages using Foxp3-GFP mice. Analysis of CD11b(+)F4/80(+)Foxp3(+) macrophage function indicated that these cells inhibited the proliferation of T cells, whereas Foxp3(-) macrophages did not. Suppression of T cell proliferation was mediated through soluble factors. Foxp3(-) macrophages acquired Foxp3 expression after activation, which conferred inhibitory properties that were indistinguishable from natural Foxp3(+) macrophages. The cytokine and transcriptional profiles of Foxp3(+) macrophages were distinct from those of Foxp3(-) macrophages, indicating that these cells have different biological functions. Functional in vivo analyses indicated that CD11b(+)F4/80(+)Foxp3(+) macrophages are important in tumor promotion and the induction of T reg cell conversion. For the first time, these studies demonstrate the existence of a distinct subpopulation of naturally occurring macrophage regulatory cells in which expression of Foxp3 correlates with suppressive function.
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
authors.forename: Soraya Zorro
authors.initials: SZ
authors.lastname: Manrique
authors.forename: Maria Adelaida Duque
authors.initials: MA
authors.lastname: Correa
authors.forename: Dominique B
authors.initials: DB
authors.lastname: Hoelzinger
authors.forename: Ana Lucia
authors.initials: AL
authors.lastname: Dominguez
authors.forename: Noweeda
authors.initials: N
authors.lastname: Mirza
authors.forename: Hsi-Hsien
authors.initials: HH
authors.lastname: Lin
authors.forename: Joan
authors.initials: J
authors.lastname: Stein-Streilein
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
authors.forename: Joseph
authors.initials: J
authors.lastname: Lustgarten
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001483:Base Sequence; D039481:CD11b Antigen / Q000378:metabolism; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D007108:Immune Tolerance / Q000502:physiology*; D008262:Macrophage Activation; D008264:Macrophages / Q000145:classification / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D039481:CD11b Antigen; D018925:Chemokines; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D034741:RNA, Small Interfering; C036763:monocyte-macrophage differentiation antigen