Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases.

• Main Authors: Robin A Welsh, Nianbin Song, Catherine A Foss, Tatiana Boronina, Robert N Cole, Scheherazade Sadegh-Nasseri
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2020-02-01
• Series: PLoS Biology
• Online Access: https://doi.org/10.1371/journal.pbio.3000590

DO (HLA-DO, in human; murine H2-O) is a highly conserved nonclassical major histocompatibility complex class II (MHC II) accessory molecule mainly expressed in the thymic medulla and B cells. Previous reports have suggested possible links between DO and autoimmunity, Hepatitis C (HCV) infection, and cancer, but the mechanism of how DO contributes to these diseases remains unclear. Here, using a combination of various in vivo approaches, including peptide elution, mixed lymphocyte reaction, T-cell receptor (TCR) deep sequencing, tetramer-guided naïve CD4 T-cell precursor enumeration, and whole-body imaging, we report that DO affects the repertoire of presented self-peptides by B cells and thymic epithelium. DO induces differential effects on epitope presentation and thymic selection, thereby altering CD4 T-cell precursor frequencies. Our findings were validated in two autoimmune disease models by demonstrating that lack of DO increases autoreactivity and susceptibility to autoimmune disease development.