Preventing the antigen-presenting function of retinal microglia blocks autoimmune neuroinflammation by dendritic...

Autoimmune uveitis is a major cause of blindness and experimental autoimmune uveitis (EAU) is mediated by interphotoreceptor retinoid-binding protein specific effector CD4⁺ T cells that infiltrate the retina. At least two MHC Class II (MHC II) antigen-presenting cell (APC) events are required for uveitis to develop. The first occurs in the secondary lymphoid organs when dendritic cells (DCs) activate and expand effector CD4⁺ T cells that enter the circulation and migrate systemically. The second APC event occurs when DC-primed effector CD4⁺ T cells infiltrate the retina and are restimulated by the relevant autoantigen. Importantly, if this second restimulation does not occur, then uveitis does not develop. However, it is still unclear which cell type(s) function as APCs within the retina. There are two candidate MHC II⁺ cell types-resident microglia and infiltrating DCs. We used the inducible Cre-lox approach to develop mouse strains in which MHC II was knocked out specifically on microglia using either the P2ry12 or Tmem119 gene to drive recombination. We also used Itgax (CD11c encoding gene) to drive recombination in DCs. Using this approach, we uncovered that the second APC event was mediated by MHC II⁺ microglia and not infiltrating MHC II⁺ DCs. Therefore, microglia are an important therapeutic target that can prevent and/or diminish uveitis even in the presence of circulating retinal autoantigen-specific effector CD4⁺ T cells.