Ectopic CD4+T cells in choroid plexus mediate neuropsychiatric lupus symptoms in mice via interferon- induced microglia activation

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a disabling and potentially life-threatening complication of SLE. This study aims to investigate whether ectopic CD4(+) T cells in the choroid plexus mediate NPSLE in mice. Intracerebroventricular (ICV) injection of anti-CD4 antibody effectively depleted CP-resident CD4(+) T cells and alleviated NPSLE-like symptoms in MRL/lpr mice. Following ICV injection, the majority of isolated lupus CD4(+) T cells from donor MRL/lpr mice predominantly stayed in the CP for at least 28 days in recipient C57BL/6 mice, while nearly all isolated CD4(+) T cells from MRL/MpJ mice disappeared within 7 days. ICV injection of lupus CD4(+) T cells resulted in NPSLE-like symptoms, including impaired behavioral performances, increased microglial activation, and abnormal microstructure changes. Flow cytometry analysis revealed that the majority of isolated lupus CD4(+) T cells were positive for IFN-gamma. Neutralizing intracerebral IFN-gamma alleviated NPSLE-like symptoms in MRL/lpr mice. Moreover, ICV injection of anti-IFN-gamma antibody or microglial depletion by PLX3397 benefited most NPSLE-like symptoms in lupus CD4(+) T-treated mice, while ICV injection of IFN-gamma mimicked most NPSLE-like symptoms. In conclusion, CP-resident lupus CD4(+) T cells contribute to NPSLE-like symptoms in mice via Interferon-gamma induced microglia activation. Depleting CP-resident lupus CD4(+) T cells, interferon-gamma, or activated microglia may be potential therapeutic targets for NPSLE.