Kurmaeva Elvira, Bhattacharya Dhruva, Goodman Wendy, Omenetti Sara, Merendino Amber, Berney Seth, Pizarro Theresa, Ostanin Dmitry V
Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA; and.
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
J Leukoc Biol. 2014 Sep;96(3):377-89. doi: 10.1189/jlb.3HI0613-340RR. Epub 2014 Apr 2.
Chronic colitis is accompanied by extensive myelopoiesis and accumulation of CD11b+Gr-1+ cells in spleens and secondary lymphoid tissues. Although cells with similar phenotype have been described in cancer, chronic infection, or autoimmunity, where they were associated with suppression of T cell responses, little is known regarding how these cells affect CD4 T cell responses in the context of chronic intestinal inflammation. Therefore, we undertook this study to characterize the interplay between colitis-induced myeloid cells and CD4 T cell. Within the CD11b+Gr-1+ population, only monocytes (Ly6G(neg)Ly6C(high)) but not other myeloid cell subsets suppressed proliferation and production of cytokines by CD4 T cells. Suppression was mediated by cell-contact, NO and partially by IFN-γ and PGs. Interestingly, Ly6C(high) MDCs, isolated from colitic colons, showed up-regulation of iNOS and arginase-1 and were more potent suppressors than those isolated from spleen. On a single-cell level, MDCs inhibited Th1 responses but enhanced generation of foxp3+ T cells. MDCs, cocultured with activated/Teffs, isolated from inflamed colons under hypoxic (1% O2) conditions typical for the inflamed intestine, suppressed proliferation but not their production of proinflammatory cytokines and chemokines. Taken together, expansion of monocytes and MDCs and activation of their suppressive properties may represent a homeostatic mechanism aimed at restraining excessive T cell activation during chronic inflammatory settings. The contribution of immunosuppressive monocytes/MDCs to chronic colitis and their role in shaping T cell responses in vivo require further investigation.
慢性结肠炎伴有广泛的骨髓生成以及脾脏和二级淋巴组织中CD11b+Gr-1+细胞的积累。尽管在癌症、慢性感染或自身免疫中已描述了具有相似表型的细胞，且它们与T细胞反应的抑制有关，但对于这些细胞在慢性肠道炎症背景下如何影响CD4 T细胞反应却知之甚少。因此，我们开展了这项研究以表征结肠炎诱导的髓样细胞与CD4 T细胞之间的相互作用。在CD11b+Gr-1+群体中，只有单核细胞（Ly6G阴性Ly6C高表达）而非其他髓样细胞亚群抑制CD4 T细胞的增殖和细胞因子产生。抑制作用由细胞接触介导，一氧化氮（NO）参与，部分还由干扰素-γ（IFN-γ）和前列腺素（PGs）介导。有趣的是，从结肠炎结肠中分离出的Ly6C高表达的髓样树突状细胞（MDCs）显示诱导型一氧化氮合酶（iNOS）和精氨酸酶-1上调，并且比从脾脏中分离出的细胞具有更强的抑制能力。在单细胞水平上，MDCs抑制Th1反应，但增强了叉头框蛋白3（foxp3）+ T细胞的生成。在典型的炎症肠道低氧（1% O2）条件下，从炎症结肠中分离出的MDCs与活化的效应性T细胞（Teffs）共培养时，抑制了其增殖，但不影响它们促炎细胞因子和趋化因子的产生。综上所述，单核细胞和MDCs的扩增及其抑制特性的激活可能代表一种稳态机制，旨在限制慢性炎症环境中过度的T细胞活化。免疫抑制性单核细胞/MDCs对慢性结肠炎的贡献及其在体内塑造T细胞反应中的作用需要进一步研究。
