Transforming growth factor-β production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte–mediated …

M Terabe, S Matsui, JM Park, M Mamura… - The Journal of …, 2003 - rupress.org
M Terabe, S Matsui, JM Park, M Mamura, N Noben-Trauth, DD Donaldson, W Chen
The Journal of experimental medicine, 2003rupress.org
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
α double KO mice showed that inhibition of immunosurveillance requires IL-13 …
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 α 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)-β, a potent inhibitor of CTL, ex vivo than such cells from naive mice, and this TGF-β production was dependent on the presence in vivo of both IL-13 and CD1d-restricted T cells. Ex vivo TGF-β production was also abrogated by depleting either CD11b+ or Gr-1+ cells from the nonlymphoid cells of tumor-bearing mice. Further, blocking TGF-β or depleting Gr-1+ cells in vivo prevented the tumor recurrence, implying that TGF-β 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-β, explains previous observations on myeloid suppressor cells or TGF-β and provides insights for targeted approaches for cancer immunotherapy, including synergistic blockade of TGF-β and IL-13.
rupress.org