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

Experimental autoimmune uveoretinitis (EAU) 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 nitric oxide (NO) by activated macrophages. The majority of immune cells infiltrating into the retina are CD11b+ myeloid cells, but, despite the presence of these antigen presenting cells, 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 signalling in the myeloid cells via TNFR1. In the absence of TNFR1 signalling, relative T cell expansion in the retina is increased, indicating that regulatory myeloid cells may also act in vivo. However, TNFR1 signalling 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 EAU induction.