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D. A. Copland, B. J. E. Raveney, A. D. Dick, L. B. Nicholson; TNFR1 Signalling Is a Critical Checkpoint in the Generation of Myeloid-Derived Suppressor Cells. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5920.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the role of myeloid regulation of T cell responses in experimental autoimmune uveoretinitis, specifically the role of TNF receptor 1 (TNFR1) signalling in the development of a subset of macrophages termed myeloid-derived suppressor cells (MDSC). Macrophages (Mϕ) and T cells are central to retinal damage during non-infectious ocular inflammation, and TNF- is critical to this destruction. We have previously demonstrated that IFNγ-mediated activation of Mϕ to produce nitric oxide (NO), which suppresses T cell proliferation, requires autocrine TNF- signaling and intact TNFR1. Furthermore, in vivo studies demonstrated CD11b+ Gr-1+ myeloid cell infiltrate during ocular inflammation, a phenotype that is characteristic of MDSC, and which suppress T cell proliferation.
To investigate the role of TNFR1 signalling in MDSC generation further, we cultured either wild type (WT) or TNFR1-/- bone-marrow derived macrophages with OVA323-339-specific TcR transgenic OT-II CD4+ T cells in the presence or absence of cognate OVA peptide. Experiments assessed cell surface marker expression, and activation of macrophages and T cells.
Activation of WT Mϕ by co-culture with T cells and cognate peptide resulted in up-regulation of Gr-1 in WT Mϕ but not TNFR1-/- Mϕ, indicating a requirement for both T cells and TNFR1 signals to generate MDSC. The suppressive mechanism by which Mϕ regulated T cells was reversible, as T cells removed from co-culture still proliferated, demonstrating that antigen presentation by Mϕ to T cells generates T cells that are poised to divide but held in check by factors within the local microenvironment. High levels of PGE2 are detected in co-cultures of WT Mϕ and T cells, but not in TNFR1-/- Mϕ co-cultures, and selective blockade of PGE2 production leads to WT Mϕ-induced T cell proliferation. Addition of exogenous PGE2 removes the requirement for TNF- signalling in the maturation of these monocytes and allows TNFR1-/- Mϕ to function as MDSC.
TNFR1 signalling is critical for the development of Mϕ that inhibit T cell proliferation. TNFR1-/- Mϕ are unable to differentiate into inhibitory MDSC because they do not produce PGE2 that provides a maturation signal, or NO, which is an essential part of the effector mechanism that inhibits T cell proliferation.
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