The role of HLA-DQ8 and B cells on CD8 IEL activation in celiac disease pathogenesis

Celiac disease (CeD) is an autoimmune-like inflammatory disorder of the small intestine that is triggered by dietary gluten and develops in genetically susceptible individuals expressing HLA-DQ2 or HLA-DQ8 molecules. 1% of the worldwide population is affected by the disease. CeD is characterized by the loss of oral tolerance to gluten manifested by HLA-DQ2 or HLA-DQ8-restricted anti-gluten inflammatory CD4 T cells in the small intestinal mucosa and by a massive expansion of cytotoxic intraepithelial CD8⁺ lymphocytes (IE-CTLs) that are involved in the killing of intestinal epithelial cells, resulting in villous atrophy (VA). Using the first transgenic CeD mouse model that recapitulates the major clinical features of CeD, including VA, we demonstrated that tissue destruction was dependent on IE-CTLs, HLA-DQ8 and B cells. To uncover the mechanisms enabling VA, we characterized IE-CTL activation during CeD development and identified a particular CD8ɑβ IEL subset that becomes activated and highly cytotoxic in a gluten and HLA-DQ8-dependant manner. Strikingly, HLA-DQ8-expressing B cells acted as antigen-presenting cells for gluten peptides and drove the sustained activation of cytotoxic CD8ɑβ IE-CTLs. Our results support a critical role of B cell-T cell interactions for CeD pathogenesis and suggest that the expression of HLA-DQ8 on B cells is required to promote cytotoxic CD8abintraepithelial lymphocyte activation and the ensuing tissue destruction in CeD.