Interleukin-15, a Master Piece in the Immunological Jigsaw of Celiac Disease

Abstract

Background: The immune response causing celiac disease (CD) depends on the activation of intestinal CD4+ T cells by gluten-derived peptides presented by HLA-DQ2 or HLA-DQ8 molecules, the main genetic risk factor. However, additional factors are necessary to impair immune tolerance to dietary gluten, to stimulate intraepithelial lymphocytes (IEL) and to induce intestinal damage. Key Messages: Current data point to a central role of interleukin-15 (IL-15). In situ and ex vivo studies indicate that IL-15 stimulates the accumulation and cytotoxic activation of CD8+ T IEL in active CD, and that of the malignant innate-like IEL in type II refractory CD (RCDII). Other studies show that IL-15 impairs the immunoregulatory control of effector T cells, notably CD8+. Recently, animal models have been designed to investigate the respective role of CD4+ T cells and IL-15 in CD. We discuss more particularly our results in such a model, which shows that IL-15 produced in excess in the intestine can cooperate with CD4+ T cells specific for a dietary antigen to trigger a celiac-like enteropathy. In this mouse model, CD4+ T cells activated by dietary ovalbumin secreted IL-2 which, along with IL-15, stimulated the expansion of noncognate intestinal cytotoxic CD8+ T cells containing large amounts of granzyme B. In the presence of IL-15, the latter cells did not respond to regulatory T cells, and accumulated in the intestine close to epithelial damage. Conclusion: On the basis of these data, we propose that, in CD, gluten-specific CD4+ T cells synthesize cytokines that synergize with IL-15 to license the expansion and activation of cytotoxic IEL, which drive tissue damage. We suggest that IL-15 is a meaningful therapeutic target, notably in patients with RCDII in which malignant IEL can respond to IL-15 independently of signals provided by CD4+ T cells.

Is adaptive-innate lymphocyte cross-talk driving mucosal disease?

“…(1) are consistent with the idea that signals derived from both innate and adaptive cells regulate the activation of innate lymphocytes in nonlymphoid tissues, and thereby contribute to mucosal inflammation and disease (6,7,9,12,15,16). This lymphocyte cross-talk is an intriguing model for the amplification of adaptive immunity and raises important mechanistic questions (further information is provided in refs.…”

Human intraepithelial lymphocytes

“…In addition to TCRαβ + CD8αβ + IEL, innate-like IEL lacking surface TCR expression were involved in the development of villous atrophy in patients with refractory CeD, 113 – 115 an indolent or cryptic innate intraepithelial lymphoma that rarely complicates CeD. In both active and refractory CeD, upregulation of IL-15 in the epithelium is thought to play a critical role in the activation of IEL and epithelial cell destruction 81 , 116 , 117 . In line with a role for IL-15 in promoting tissue destruction, a study showed that when mice overexpressing IL-15 in the epithelium were crossed to ovalbumin-specific CD4 TCR transgenic mice, they developed villous atrophy when ingesting ovalbumin 118 .…”

Intestinal T‐cell lymphoma with enteropathy‐associated T‐cell lymphoma‐like features arising in the setting of adult autoimmune enteropathy

“…Enteropathy-associated T-cell lymphoma arising in the setting of CD is considered as the end phase of a biological process characterized by the development of an intraepithelial T-cell clone that first gives rise to sustained cytolytic attack, then develops genetic abnormalities and finally progresses to a clinically and histologically aggressive neoplasm. 13 In this scenario, the onset of a T-cell lymphoma with the features of EATL within the setting of adult AE is of great interest, even though only 1 report is present in the literature, possibly because of the rarity of this condition. 2 Herein, we describe the second case where, after a long course of clinical, serological, and histological remission, the appearance of a monoclonal rearrangement of the TCR-γ was followed by a rapid transition to an overt lymphoma carrying the classic CD30 marker and expressing the cytotoxic molecules.…”