Celiac disease (CeD) is a complex intestinal inflammatory disorder 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 this disease for which the only effective treatment is a lifelong and restrictive gluten-free diet (GFD). Yet, persistent symptoms and enteropathy remain commonplace even among CeD patients that adhere to a GFD. This stresses the need to develop non-dietary interventions for CeD. The development of new therapies for CeD has however proven challenging because of our incomplete understanding of the mechanisms underlying the pathogenesis of the disease (particularly the factors leading to villous atrophy). 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 that are involved in the killing of intestinal epithelial cells. Cytotoxic intraepithelial lymphocytes mediated-tissue destruction is dependent on B cells and HLA-DQ8 in a mouse model of CeD.

To further uncover the mechanisms enabling villous atrophy, we have characterized cytotoxic intraepithelial CD8⁺ lymphocytes activation during CeD development and identified a particular CD8ɑβ IEL subset that becomes activated and highly cytotoxic in a gluten and HLA-DQ8-dependent manner. The activation of CD8ɑβhi intraepithelial lymphocytes is driven by B cells expressing HLA-DQ8 that can act as antigen-presenting cells for gluten peptides. 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 CD8ɑβ intraepithelial lymphocyte activation and the ensuing tissue destruction in CeD.