The Role of Autoimmunity-Related Gene <i>CLEC16A</i> in the B Cell Receptor–Mediated HLA Class II Pathway

Abstract

C-type lectin <i>CLEC16A</i> is located next to <i>CIITA</i>, the master transcription factor of HLA class II (HLA-II), at a susceptibility locus for several autoimmune diseases, including multiple sclerosis (MS). We previously found that <i>CLEC16A</i> promotes the biogenesis of HLA-II peptide-loading compartments (MIICs) in myeloid cells. Given the emerging role of B cells as APCs in these diseases, in this study, we addressed whether and how <i>CLEC16A</i> is involved in the BCR-dependent HLA-II pathway. <i>CLEC16A</i> was coexpressed with surface class II-associated invariant chain peptides (CLIP) in human EBV-positive and not EBV-negative B cell lines. Stable knockdown of <i>CLEC16A</i> in EBV-positive Raji B cells resulted in an upregulation of surface HLA-DR and CD74 (invariant chain), whereas CLIP was slightly but significantly reduced. In addition, IgM-mediated <i>Salmonella</i> uptake was decreased, and MIICs were less clustered in <i>CLEC16A</i>-silenced Raji cells, implying that <i>CLEC16A</i> controls both HLA-DR/CD74 and BCR/Ag processing in MIICs. In primary B cells, <i>CLEC16A</i> was only induced under CLIP-stimulating conditions in vitro and was predominantly expressed in CLIP^high naive populations. Finally, CLIP-loaded HLA-DR molecules were abnormally enriched, and coregulation with <i>CLEC16A</i> was abolished in blood B cells of patients who rapidly develop MS. These findings demonstrate that CLEC16A participates in the BCR-dependent HLA-II pathway in human B cells and that this regulation is impaired during MS disease onset. The abundance of CLIP already on naive B cells of MS patients may point to a chronically induced stage and a new mechanism underlying B cell-mediated autoimmune diseases such as MS.