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

• Published in: PLoS biology 2020-02, Vol.18 (2), p.e3000590-e3000590
• Main Authors: Welsh, Robin A, Song, Nianbin, Foss, Catherine A, Boronina, Tatiana, Cole, Robert N, Sadegh-Nasseri, Scheherazade
• Format: Article
• Language: English
• Subjects: Animals; Antigen presentation; Antigen-Presenting Cells - immunology; Antigenic determinants; Antigens; Autoimmune diseases; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmunity; Autoimmunity - genetics; B cells; B-Lymphocytes - immunology; Biology and Life Sciences; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Collagen - administration & dosage; Collagen - immunology; Development and progression; Diagnostic reagents industry; Disease; Disease Models, Animal; Disease susceptibility; Elution; Enumeration; Epithelium; Epitopes; Experiments; Genetic Predisposition to Disease - genetics; Health aspects; Hepatitis; Hepatitis C; Hepatitis C virus; Histocompatibility antigen HLA; Histocompatibility Antigens Class II - genetics; Immunology; Lymphocytes; Lymphocytes B; Lymphocytes T; Major histocompatibility complex; Mass spectrometry; Medical research; Medicine; Medicine and Health Sciences; Medicine, Experimental; Medulla; Medulla oblongata; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mixed leukocyte reaction; Myelin-Oligodendrocyte Glycoprotein - immunology; Peptides; Peptides - immunology; Precursor Cells, T-Lymphoid - immunology; Precursors; Proteomics; Research and Analysis Methods; Scientific imaging; T cell receptors; T cells; T-cell receptor; Thymus; Thymus Gland - immunology
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 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.