title: Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence.
abstract: Our previous work demonstrated that cytotoxic T lymphocyte (CTL)-mediated tumor immunosurveillance of the 15-12RM tumor could be suppressed by a CD1d-restricted lymphocyte, most likely a natural killer (NK) T cell, which produces interleukin (IL)-13. Here we present evidence for the effector elements in this suppressive pathway. T cell-reconstituted recombination activating gene (RAG)2 knockout (KO) and RAG2/IL-4 receptor alpha double KO mice showed that inhibition of immunosurveillance requires IL-13 responsiveness by a non-T non-B cell. Such nonlymphoid splenocytes from tumor-bearing mice produced more transforming growth factor (TGF)-beta, a potent inhibitor of CTL, ex vivo than such cells from naive mice, and this TGF-beta production was dependent on the presence in vivo of both IL-13 and CD1d-restricted T cells. Ex vivo TGF-beta production was also abrogated by depleting either CD11b+ or Gr-1+ cells from the nonlymphoid cells of tumor-bearing mice. Further, blocking TGF-beta or depleting Gr-1+ cells in vivo prevented the tumor recurrence, implying that TGF-beta made by a CD11b+ Gr-1+ myeloid cell, in an IL-13 and CD1d-restricted T cell-dependent mechanism, is necessary for down-regulation of tumor immunosurveillance. Identification of this stepwise regulation of immunosurveillance, involving CD1-restricted T cells, IL-13, myeloid cells, and TGF-beta, explains previous observations on myeloid suppressor cells or TGF-beta and provides insights for targeted approaches for cancer immunotherapy, including synergistic blockade of TGF-beta and IL-13.
authors.affiliation: Molecular Immunogenetics and Vaccine Research Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Terabe
authors.forename: So
authors.initials: S
authors.lastname: Matsui
authors.forename: Jong-Myun
authors.initials: JM
authors.lastname: Park
authors.forename: Mizuko
authors.initials: M
authors.lastname: Mamura
authors.forename: Nancy
authors.initials: N
authors.lastname: Noben-Trauth
authors.forename: Debra D
authors.initials: DD
authors.lastname: Donaldson
authors.forename: Wanjun
authors.initials: W
authors.lastname: Chen
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Wahl
authors.forename: Steven
authors.initials: S
authors.lastname: Ledbetter
authors.forename: Bruce
authors.initials: B
authors.lastname: Pratt
authors.forename: John J
authors.initials: JJ
authors.lastname: Letterio
authors.forename: William E
authors.initials: WE
authors.lastname: Paul
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
mesh_terms: D000818:Animals; D018949:Antigens, CD1 / Q000276:immunology*; D055610:Antigens, CD1d; D001854:Bone Marrow Cells / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D016130:Immunophenotyping; D018793:Interleukin-13 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D012008:Recurrence; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; D018793:Interleukin-13; D016212:Transforming Growth Factor beta