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.
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.
Terabe
Masaki
M
Molecular Immunogenetics and Vaccine Research Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Matsui
So
S
Park
Jong-Myun
JM
Mamura
Mizuko
M
Noben-Trauth
Nancy
N
Donaldson
Debra D
DD
Chen
Wanjun
W
Wahl
Sharon M
SM
Ledbetter
Steven
S
Pratt
Bruce
B
Letterio
John J
JJ
Paul
William E
WE
Berzofsky
Jay A
JA
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
D018949:Antigens, CD1; D055610:Antigens, CD1d; D018793:Interleukin-13; D016212:Transforming Growth Factor beta