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B. J. Raveney, L. B. Nicholson, A. D. Dick; Control of Auto-Reactive CD4+ T Cell Proliferation by Macrophages in Target Organs. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3625.
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Macrophages and T cells are central to retinal damage during non-infectious ocular inflammation; TNFα is also critical to such tissue destruction. We investigated the rôle of TNFα signalling in controlling the immune response that follows macrophage interaction with T cells in the target organ. In experimental autoimmune uveoretinitis (EAU), macrophages act as antigen presenting cells and are in addition activated by inflammatory cytokines contributing to tissue damage. We have previously demonstrated that IFNγ-mediated activation of macrophages to produce nitric oxide relies on signalling through autocrine TNFα; thus TNFR1-/- macrophages are less sensitive to IFNγ activation. To date, studies have not directly addressed the consequences of interactions between T cells and macrophages in the target organ, which are critical in determining clinical outcome.
Using an in vitro correlate of ocular inflammation, we have cultured retinal antigen-specific CD4+ T cell clones with macrophages derived from bone marrow of wild type or TNFR1-/- mice. Experiments assessed both the antigen-specific activation of T cells by macrophages, and macrophage activation under inflammatory conditions.
T cell proliferation is inhibited, yet the IFNγ response is maintained, when retinal antigen-specific CD4+ T cell were activated by wild type macrophages in the presence of cognate antigen. In contrast to wild type macrophages, TNFR1-/- macrophages, as well as professional antigen presenting cells, generated T cell proliferative antigen-specific responses. We have identified and characterised the TNFα-dependant mechanisms by which activated macrophages can regulate T cell activation, which include production of nitric oxide (NO) and secretion of prostaglandins.
The outcomes of antigen presentation in target organs are substantially different to the outcomes of similar activation in secondary lymphoid tissue. The mechanisms by which macrophages limit T cell activation may be an important therapeutic target to treat ocular inflammation.
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