Figure 2. Mechanisms driving activation and malignant transformation of intraepithelial lymphocytes in celiac disease and type II refractory celiac disease.

In celiac disease (CeD) and type II refractory CeD (RCDII), CD4 ⁺ T cells are activated by gluten peptides modified by transglutaminase-2 (TG2) and loaded onto HLA-DQ2.5/DQ8 molecules at the surface of antigen-presenting cells. Activation of CD4 ⁺ T cells harboring cognate T-cell receptors (TCRs) for gluten peptides is likely initiated by dendritic cells (DCs) in gut-lymphoid tissue or mesenteric lymph nodes (not shown). Primed gluten-specific CD4 ⁺ T cells may then home into the gut lamina propria. Upon reactivation by gluten peptides presented by DCs or perhaps by plasma cells ³⁶, the latter cells secrete cytokines—interleukin-2 (IL-2), IL-21, and interferon gamma (IFNγ)—which can cooperate with IL-15, produced notably by epithelial cells (ECs), to activate cytotoxic intraepithelial lymphocytes (IELs) and license enterocyte killing. In uncomplicated CeD, IL-2 and IL-21 cooperate with IL-15 to stimulate cytotoxic CD8 ⁺TCRαβ ⁺ IELs expressing natural killer receptors (NKRs). In RCDII, somatic JAK1 or STAT3 gain-of-function (gof) mutations, which confer hyper-responsiveness to IL-15, IL-2, and IL-21, allow a clone of innate-like T-IELs to progressively out-compete normal T-IELs and invade the epithelium. Major histocompatibility complex class I polypeptide-related sequence A (MICA), which is induced by stress, and HLA-E which is induced by IFNγ, are two NKR ligands that are upregulated on ECs in active CeD and in RCD. Their expression promotes enterocyte killing by T-IELs in CeD, and by malignant innate-like T-IELs in RCDII. During their expansion in the gut epithelium, RCDII IELs can acquire additional mutations, which promote their transformation into aggressive enteropathy-associated lymphoma (EATL).