Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 198, Issue 11, Pages 1741-1752Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20022227
Keywords
TGF-beta; NKT cells; immunologic surveillance; myeloid cells; IL-13
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Funding
- NATIONAL CANCER INSTITUTE [ZIASC004020, Z01SC004020] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000493, Z01AI000493] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [ZIADE000046] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH [Z01DE000046, Z01DE000691] Funding Source: NIH RePORTER
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Our previous work demonstrated that cytotoxic T lymphocyte (CTL)-niediated tumor immunosurveillance of the 15-12PM 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.
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