Extended Data Fig. 11: Interplay between IL-15, TG2 and HLA-DQ8 promote the development of villous atrophy.

a, Representation of the respective roles of HLA-DQ8, IL-15, IFNγ, TG2, CD4⁺ and CD8⁺ T cells in promoting villous atrophy. IL-15 upregulation in the lamina propria is required to induce the adaptive anti-gluten T_H1 response, and HLA-DQ8 facilitates and enhances the IFNγ response that is required for the development of villous atrophy. However, the adaptive T_H1 immune response promoted by HLA-DQ8 and IL-15 in the lamina propria is insufficient to cause tissue destruction. It needs to synergize with IL-15 in the epithelium to further promote the expansion of cytolytic IELs and their degranulation, leading to CD8⁺ T cell-dependent killing of epithelial cells and villous atrophy. The value of this mouse model as a gluten- and HLA-DQ8-dependent pre-clinical model for coeliac disease is further emphasized by the finding that TG2 inhibition prevents villous atrophy. b, Coeliac disease can be represented as a jigsaw puzzle in which each piece representing one component of the anti-gluten immune response must interlock to lead to the development of villous atrophy—the diagnostic hallmark of active coeliac disease.