Neoself-antigens are the primary target for autoreactive T cells in human lupus

Major histocompatibility complex class II (MHC-II) is the most significant genetic risk factor for systemic lupus erythematosus (SLE), but the nature of the self-antigens that trigger autoimmunity remains unclear. Unusual self-antigens, termed neoself-antigens, are presented on MHC-II in the absence of the invariant chain essential for peptide presentation. Here, we demonstrate that neoself-antigens are the primary target for autoreactive T cells clonally expanded in SLE. When neoself-antigen presentation was induced by deleting the invariant chain in adult mice, neoself-reactive T cells were clonally expanded, leading to the development of lupus-like disease. Furthermore, we found that neoself-reactive CD4+ T cells were significantly expanded in SLE patients. A high frequency of Epstein-Barr virus reactivation is a risk factor for SLE. Neoself-reactive lupus T cells were activated by Epstein-Barr-virus-reactivated cells through downregulation of the invariant chain. Together, our findings imply that neoself-antigen presentation by MHC-II plays a crucial role in the pathogenesis of SLE. We performed scRNA sequencing to understand the effect of MHC-class II dysfunction on autoimmunity. details of the HTO antibodies HTO: barcode sequence: hashtagged sample (condition/treatment) TotalSeq-C0301 anti-mouse Hashtag 1 Antibody: ACCCACCAGTAAGAC: mouse splenic CD4 T cells isolated by magnetic beads, replicate 1 TotalSeq-C0304 anti-mouse Hashtag 4 Antibody: AAAGCATTCTTCACG: mouse splenic CD4 T cells isolated by magnetic beads, replicate 2 TotalSeq-C0306 anti-mouse Hashtag 6 Antibody: TATGCTGCCACGGTA: mouse splenic CD4 T cells isolated by magnetic beads, replicate 3