Targeting the CD80/CD86 costimulatory pathway with CTLA4‐Ig directs microglia toward a repair phenotype and promotes axonal outgrowth

Among the costimulatory factors widely studied in the immune system is the CD28/cytotoxic T‐lymphocyte antigen‐4 (CTLA4)‐CD80/CD86 pathway, which critically controls the nature and duration of the T‐cell response. In the brain, up‐regulated expression of CD80/CD86 during inflammation has consistently been reported in microglia. However, the role of CD80/CD86 molecules has mainly been studied in a context of microglia‐T cell interactions in pathological conditions, while the function of CD80/CD86 in the regulation of intrinsic brain cells remains largely unknown. In this study, we used a transgenic pig line in which neurons express releasable CTLA4‐Ig, a synthetic molecule mimicking CTLA4 and binding to CD80/CD86. The effects of CTLA4‐Ig on brain cells were analyzed after intracerebral transplantation of CTLA4‐Ig‐expressing neurons or wild‐type neurons as control. This model provided in vivo evidence that CTLA4‐Ig stimulated axonal outgrowth, in correlation with a shift of the nearby microglia from a compact to a ramified morphology. In a culture system, we found that the CTLA4‐Ig‐induced morphological change of microglia was mediated through CD86, but not CD80. This was accompanied by microglial up‐regulated expression of the anti‐inflammatory molecule Arginase 1 and the neurotrophic factor BDNF, in an astrocyte‐dependent manner through the purinergic P2Y₁ receptor pathway. Our study identifies for the first time CD86 as a key player in the modulation of microglia phenotype and suggests that CTLA4‐Ig‐derived compounds might represent new tools to manipulate CNS microglia. GLIA 2015;63:2298–2312