Final Report Summary - T_CELL(S)_DIFFER (Differentiation of pro-inflammatory T cell subsets in vivo)
T cells orchestrate immune responses to infections and tumours by producing pro-inflammatory cytokines such as interferon-g (IFN-g) and interleukin-17 (IL-17). In this project we have investigated the molecular mechanisms responsible for the generation of T cells selectively endowed with IFN-g or IL-17-production in vivo, with an emphasis on the still poorly understood gd T cell lineage.
Among several experimental strategies, we have undertaken the first genome-wide characterization the histone modifications present in IFN-g versus IL-17-producing gd T cell subsets, which we have shown to be distinguishable on the basis of surface CD27 expression levels. We demonstrated that CD27+ gd T cells are epigenetically committed to Ifng (but not Il17) expression, whereas CD27- gd T cells acquire Il17 expression in the thymus but can be induced to co-produce IFN-g under strong inflammatory conditions mediated by the cytokines IL-1b and IL-23. These signature molecular profiles included differential expression of master transcription factors; and translated into distinct cellular phenotypes in the tumor microenvironment, namely in ovarian cancer.
We further dissected the behaviour of CD27+ versus CD27- gd T cells in various tumour models: whereas in the B16 melanoma model, IFN-g-producing CD27+ gd T cells played a host-protective role in tumour progression, in the ID8 ovarian cancer model we found an unexpected pro-tumoural role of IL-17-producing CD27- gd T cells through recruitment of small peritoneal macrophages that enhanced tumour proliferation and angiogenesis. This raised unprecedented awareness of the pleiotropic roles of gd T cells in cancer.
Collectively, the results of this project have provided major advances to our understanding of the differentiation of pro-inflammatory gd T cell subsets in vivo; and have major implications for their manipulation in cancer immunotherapy.
Among several experimental strategies, we have undertaken the first genome-wide characterization the histone modifications present in IFN-g versus IL-17-producing gd T cell subsets, which we have shown to be distinguishable on the basis of surface CD27 expression levels. We demonstrated that CD27+ gd T cells are epigenetically committed to Ifng (but not Il17) expression, whereas CD27- gd T cells acquire Il17 expression in the thymus but can be induced to co-produce IFN-g under strong inflammatory conditions mediated by the cytokines IL-1b and IL-23. These signature molecular profiles included differential expression of master transcription factors; and translated into distinct cellular phenotypes in the tumor microenvironment, namely in ovarian cancer.
We further dissected the behaviour of CD27+ versus CD27- gd T cells in various tumour models: whereas in the B16 melanoma model, IFN-g-producing CD27+ gd T cells played a host-protective role in tumour progression, in the ID8 ovarian cancer model we found an unexpected pro-tumoural role of IL-17-producing CD27- gd T cells through recruitment of small peritoneal macrophages that enhanced tumour proliferation and angiogenesis. This raised unprecedented awareness of the pleiotropic roles of gd T cells in cancer.
Collectively, the results of this project have provided major advances to our understanding of the differentiation of pro-inflammatory gd T cell subsets in vivo; and have major implications for their manipulation in cancer immunotherapy.