Meresse Bertrand, Korneychuk Natalia, Malamut Georgia, Cerf-Bensussan Nadine
Dig Dis. 2015;33(2):122-130. doi: 10.1159/000369521. Epub 2015 Apr 22.
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.
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.
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.
导致乳糜泻（CD）的免疫反应取决于由HLA - DQ2或HLA - DQ8分子呈递的麸质衍生肽激活肠道CD4 + T细胞，HLA - DQ2或HLA - DQ8分子是主要的遗传风险因素。然而，还需要其他因素来损害对膳食麸质的免疫耐受、刺激上皮内淋巴细胞（IEL）并诱导肠道损伤。
目前的数据表明白细胞介素-15（IL - 15）起核心作用。原位和体外研究表明，IL - 15刺激活动性CD中CD8 + T IEL以及II型难治性CD（RCDII）中恶性天然样IEL的积累和细胞毒性激活。其他研究表明，IL - 15损害效应T细胞尤其是CD8 + T细胞的免疫调节控制。最近，已设计动物模型来研究CD4 + T细胞和IL - 15在CD中的各自作用。我们更特别地讨论了在这样一个模型中的结果，该模型表明肠道中过量产生的IL - 15可与针对膳食抗原的CD4 + T细胞协同作用，引发类似乳糜泻的肠病。在这个小鼠模型中，由膳食卵清蛋白激活的CD4 + T细胞分泌IL - 2，IL - 2与IL - 15一起刺激含有大量颗粒酶B的非同源肠道细胞毒性CD8 + T细胞的扩增。在有IL - 15存在的情况下，后一种细胞对调节性T细胞无反应，并在靠近上皮损伤的肠道中积累。
基于这些数据，我们提出，在CD中，麸质特异性CD4 + T细胞合成与IL - 15协同作用的细胞因子，以许可细胞毒性IEL的扩增和激活，从而导致组织损伤。我们认为IL - 15是一个有意义的治疗靶点，特别是在RCDII患者中，其中恶性IEL可独立于CD4 + T细胞提供的信号对IL - 15作出反应。
