T-cell Expression of IL10 Is Essential for Tumor Immune Surveillance in the Small Intestine.
T-cell Expression of IL10 Is Essential for Tumor Immune Surveillance in the Small Intestine.
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DOI：
10.1158/2326-6066.cir-14-0169
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发表时间：
2015-07
影响因子：
10.1
通讯作者：
Khazaie K
中科院分区：
文献类型：
--
作者：
Dennis KL;Saadalla A;Blatner NR;Wang S;Venkateswaran V;Gounari F;Cheroutre H;Weaver CT;Roers A;Egilmez NK;Khazaie K
IL10具有免疫抑制和抗炎作用，可促进或抑制胃肠道肿瘤。IL10的缺失会加剧结肠炎和癌症。与此一致的是，将IL10能力调节T细胞(Treg)转移到患有结肠炎或遗传性息肉病的小鼠体内可以预防疾病，而IL10缺陷小鼠更容易患上息肉病，结肠息肉负荷增加。关于IL10在小肠癌中的保护或致病作用，人们知之甚少。我们发现CD_4+T细胞和CD_4+FOXP_3+T细胞是小肠IL-10的主要来源，并与遗传性息肉病Δ-468小鼠模型息肉时IL-10的升高有关。靶向消融T细胞中的IL10会导致严重的IL10缺乏和息肉生长延迟。然而，这些息肉逐渐失去了细胞毒活性，最终发展为癌症。一些观察表明，这种效果是由于失去了对干扰素γ依赖的免疫监视。IL 10无功能的CD 4+T细胞在息肉抗原刺激下不能分泌干扰素γ，也不能有效地分泌Th1。相比之下，TH17的承诺没有受到影响。这些发现在T细胞过度表达IL10的小鼠身上得到了验证。在这些小鼠中，我们观察到息肉内的高细胞毒活性和息肉病的减弱。因此，T细胞表达IL10是保护性的，是小肠免疫监测所必需的。
IL10 is attributed with immune suppressive and anti-inflammatory properties, which could promote or suppress cancer in the gastrointestinal tract. Loss of IL10 exacerbates colonic inflammation leading to colitis and cancer. Consistent with this, transfer of IL10-competent regulatory T cells (Treg) into mice with colitis or hereditary polyposis protects against disease, while IL10-deficient mice are predisposed to polyposis with increased colon polyp load. Little is known about the protective or pathogenic function of IL10 in cancers of the small intestine. We found CD4+ T cells and CD4+ Foxp3+ Tregs to be the major sources of IL10 in the small intestine and responsible for the increase in IL10 during polyposis in the APCΔ468 mouse model of hereditary polyposis. Targeted ablation of IL10 in T cells caused severe IL10 deficiency and delayed polyp growth. However, these polyps progressively lost cytotoxic activity and eventually progressed to cancer. Several observations suggested that the effect was due to the loss of IFNγ-dependent immune surveillance. IL10 incompetent CD4+ T cells failed to secrete IFNγ when stimulated with polyp antigens and were inefficient in TH1 commitment. By contrast, the TH17 commitment was unaffected. These findings were validated using mice whose T cells overexpress IL10. In these mice, we observed high intra-polyp cytotoxic activity and attenuation of polyposis. Thus, expression of IL10 by T cells is protective and required for immune surveillance in the small intestine.