TNFR1-Dependent Regulation of Myeloid Cell Function in Experimental Autoimmune Uveoretinitis

Experimental autoimmune uveoretinitis is an autoimmune disease induced in mice, which involves the infiltration of CD11b(+) macrophages and CD4(+) T cells into the normally immune-privileged retina. Damage is produced in the target organ following the activation of Th1 and Th17 T cells and by the release of cytotoxic mediators such as NO by activated macrophages. The majority of immune cells infiltrating into the retina are CD11b(+) myeloid cells, but, despite the presence of these APCs, relatively limited numbers of T cells are observed in the retina during the disease course. These T cells do not proliferate when leukocytes are isolated from the retina and restimulated in vitro, although they do produce both IFN-gamma and IL-17. T cell proliferation was restored by depleting the myeloid cells from the cultures and furthermore those isolated myeloid cells were able to regulate the proliferation of other T cells. The ability of macrophages to regulate proliferation depends on activation by T cell-produced IFN-gamma and autocrine TNF-alpha signaling in the myeloid cells via TNFR1. In the absence of TNFR1 signaling, relative T cell expansion in the retina is increased, indicating that regulatory myeloid cells may also act in vivo. However, TNFR1 signaling is also required for macrophages, but not T cells, to migrate into the target organ. Thus, in TNFR1 knock out mice, the amplification of autoimmunity is limited, leading to resistance to experimental autoimmune uveoretinitis induction. The Journal of Immunology, 2009, 183: 2321-2329.