Negative feedback regulation of colitogenic CD4+ T cells by increased granulopoiesis
Negative feedback regulation of colitogenic CD4+ T cells by increased granulopoiesis
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DOI：
10.1002/ibd.20531
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发表时间：
2008-11
影响因子：
4.9
通讯作者：
Y. Nemoto;T. Kanai;S. Tohda;T. Totsuka;R. Okamoto;K. Tsuchiya;Tetsuya Nakamura;N. Sakamoto;T. Fukuda;O. Miura;H. Yagita;Mamoru Watanabe
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作者：
Y. Nemoto;T. Kanai;S. Tohda;T. Totsuka;R. Okamoto;K. Tsuchiya;Tetsuya Nakamura;N. Sakamoto;T. Fukuda;O. Miura;H. Yagita;Mamoru Watanabe
背景：慢性炎症性疾病的特点是炎症部位大量先天免疫细胞和获得性免疫细胞的侵袭。然而，目前还不清楚这些细胞在疾病发展中是如何合作的。虽然骨髓(BM)是除T细胞外的免疫细胞的主要造血点，但BM从外周招募记忆T细胞。我们最近证实，在结肠性CD4+CD45RBHigh T细胞转移的SCID小鼠的骨髓中存在结肠性CD4+记忆T细胞。基于这一背景，我们在此研究粒细胞是促进还是抑制了结肠性CD4+T细胞的增殖。方法：首先，我们发现Gr-1HighCD11b+粒细胞在结肠炎BM中显著增加，同时外周血粒细胞也显著增加。克隆形成单位(CFU)分析显示，粒细胞集落形成主要由抗CD3刺激的结肠炎BM CD4+T细胞的培养上清液诱导。结果：应用去粒细胞抗Gr-1单抗治疗结肠炎小鼠并没有改善结肠炎的症状，而是增加了表型活化的CD4+T细胞的扩增，而不是固有层，从而加剧了疾病的消退。结论：结肠性BM CD4+T细胞促进粒系生成是控制全身炎症反应的负反馈机制。
Background: Chronic inflammatory diseases are characterized by massive infiltration of innate and acquired immune cells in inflammatory sites. However, it remains unclear how these cells cooperate in the development of disease. Although bone marrow (BM) is a primary site for hematopoiesis of immune cells except T cells, BM recruits memory T cells from the periphery. We have recently demonstrated that colitogenic CD4+ memory T cells reside in BM of colitic CD4+CD45RBhigh T‐cell‐transferred SCID mice. Based on this background we here investigate whether granulocytes promote or suppress the expansion of colitogenic CD4+ T cells. Methods: First, we show that Gr‐1highCD11b+ granulocytes were significantly increased in colitic BM along with a significant increase of peripheral granulocytes. Consistently, the colony‐forming unit (CFU) assay revealed that granulocyte colony formation was dominantly induced by supernatants from anti‐CD3‐stimulated colitic BM CD4+ T cells. Results: Administration of granulocyte‐depleting anti‐Gr‐1 mAb to colitic mice did not ameliorate the colitis, but exacerbated the wasting disease with an increased expansion of systemic, but not lamina propria, CD4+ T cells with activated phenotype. Conclusions: These results suggest that the increased granulopoiesis by colitogenic BM CD4+ T cells represent a negative feedback mechanism to control systemic inflammation.