title: Rat CD4+CD8+ macrophages kill tumor cells through an NKG2D- and granzyme/perforin-dependent mechanism.
abstract: We previously identified a subpopulation of monocyte/macrophage lineage cells expressing both CD4 and CD8. This subpopulation was expanded in rat peripheral blood and spleen after immunization with adjuvants containing killed tuberculosis germs. CD4+CD8+ monocytes/macrophages obtained from preimmunized rats exhibited a Th1-type cytokine/chemokine profile, expressed high levels of Fas ligand, perforin, granzyme B, and NKR-P2 (rat ortholog of human NKG2D), and killed certain tumor cells. In the present study, we confirmed that CD4+CD8+ monocytes/macrophages are distinct from splenic dendritic cells (DCs) or IFN-producing killer DCs. In vitro cytotoxic assays revealed that CD4+CD8+ macrophages killed tumor cells in a cell-cell contact-dependent manner and that expression of the retinoic acid early transcript 1 (a ligand for NKG2D) made tumor cells susceptible to killing by CD4+CD8+ macrophages. Furthermore, inhibitors of granzyme and perforin significantly decreased cytotoxic activities of CD4+CD8+ macrophages. Consistent with these in vitro findings, preimmunization with adjuvants containing killed tuberculosis germs elevated the expression of granzyme B in tumor-infiltrating CD4+CD8+ macrophages and significantly inhibited the growth of inoculated tumor cells. Our current work demonstrates that CD4+CD8+ macrophages are a unique subpopulation of monocyte/macrophage lineage cells that kill tumor cells in an NKG2D- and granzyme/perforin-dependent mechanism.
authors.affiliation: Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Baba
authors.forename: Sari
authors.initials: S
authors.lastname: Iwasaki
authors.forename: Takako
authors.initials: T
authors.lastname: Maruoka
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.forename: Utano
authors.initials: U
authors.lastname: Tomaru
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ikeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshiki
authors.forename: Masanori
authors.initials: M
authors.lastname: Kasahara
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ishizu
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000096:biosynthesis*; D019556:COS Cells; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D053804:Granzymes / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000502:physiology*; D008024:Ligands; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K; D054353:Perforin / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000502:physiology*; D055607:Receptors, Natural Killer Cell
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D006131:Growth Inhibitors; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D037181:Lectins, C-Type; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; C113208:NKR-P2 protein, rat; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D054353:Perforin; D053804:Granzymes