Benaroya Research Institute, Translational Research Program, United States..
Benaroya Research Institute, Translational Research Program, United States.
Clin Immunol. 2018 Aug;193:24-32. doi: 10.1016/j.clim.2018.05.006. Epub 2018 May 26.
Integrin alpha4/beta7 on circulating lymphocytes identifies them as gut-tropic, and can be targeted by the humanized antibody vedolizumab to treat inflammatory bowel disease (IBD). We found lymphocytes expressing alpha4/beta7 were significantly more responsive to the pro-inflammatory cytokines IL-6, IL-7, and IL-21, and less responsive to the regulatory T cell (Treg)-supporting cytokine IL-2. Alpha4/beta7 was expressed by a smaller percent of FOXP3 + Helios+ thymically-derived Tregs (tTregs) than FOXP3 + Helios- peripherally-derived Tregs (pTregs) or FOXP3- effector T cells. Integrin alpha4/beta7+ CD4 T cells were also rare among cells expressing the Th2 marker CRTh2, but enriched in cells bearing the circulating T follicular helper cell marker CXCR5. Thus the effect of this anti-integrin therapy on the mucosal immune system may be more qualitative than quantitative, and selectively replace pro-inflammatory effector cells with Tregs and Th2 cells to facilitate immune tolerance in the mucosa without globally depleting lymphocytes from the intestinal mucosa.
整合素α4/β7 在循环淋巴细胞上的表达将其鉴定为肠道趋向性，并且可以被人源化抗体 vedolizumab 靶向，用于治疗炎症性肠病（IBD）。我们发现表达α4/β7 的淋巴细胞对促炎细胞因子 IL-6、IL-7 和 IL-21 的反应更敏感，而对调节性 T 细胞（Treg）支持细胞因子 IL-2 的反应更不敏感。整合素α4/β7 在 FOXP3⁺Helios⁺胸腺来源的调节性 T 细胞（tTregs）中的表达比例低于 FOXP3⁺Helios-外周来源的调节性 T 细胞（pTregs）或 FOXP3-效应 T 细胞。整合素α4/β7+CD4 T 细胞在表达 Th2 标志物 CRTh2 的细胞中也很少见，但在携带循环滤泡辅助 T 细胞标志物 CXCR5 的细胞中富集。因此，这种抗整合素治疗对黏膜免疫系统的影响可能更多是定性的，而不是定量的，它可以选择性地用 Tregs 和 Th2 细胞替代促炎效应细胞，从而促进黏膜免疫耐受，而不会从肠道黏膜中普遍耗尽淋巴细胞。
