Mature cystic fibrosis airway neutrophils suppress T cell function: evidence for a role of arginase 1 but not programmed death-ligand 1.
Mature cystic fibrosis airway neutrophils suppress T cell function: evidence for a role of arginase 1 but not programmed death-ligand 1.
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DOI：
10.4049/jimmunol.1500312
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发表时间：
2015-06-01
期刊：
影响因子：
--
通讯作者：
Tirouvanziam R
中科院分区：
文献类型：
--
作者：
Ingersoll SA;Laval J;Forrest OA;Preininger M;Brown MR;Arafat D;Gibson G;Tangpricha V;Tirouvanziam R
细菌定植于囊性纤维化(CF)的呼吸道，尽管引流淋巴结中存在具有适当抗原特异性的T细胞，但腔内明显缺乏这些T细胞。为了解释这种缺失，我们假设中性粒细胞(PMN)大量募集到CF气道腔并活跃地排出初级颗粒，也抑制了其中的T细胞功能。晚期发挥T细胞抑制作用的程序性死亡配体1(PD-L1)在肺泡灌洗液中呈双峰表达，分为PD-L1hi和PD-L1lo两个亚群，而健康对照(HC)的PMN均为PD-L1hi。在CF气道液中孵育的血液PMN随着时间的推移失去PD-L1，在共培养中，PD-L1的抗体阻断不能抑制CF气道液对T细胞增殖的抑制。与PD-L1相比，在早期发挥T细胞抑制作用的精氨酸酶1(Arg1)在CF型和HC气道型PMN上均呈高表达。然而，精氨酸酶活性在CF气道液中很高，在HC气道液中很低，这与Arg1激活需要初级颗粒胞吐的事实相一致，这一事实发生在CF而不是HC的气道PMN中。CFPMN Arg1表达与肺功能呈负相关，与CF气道液中精氨酸酶活性呈正相关。精氨酸酶抑制剂和精氨酸联合治疗可挽救CF气道液对T细胞增殖的抑制作用。因此，Arg1和PD-L1在PMN迁移到人类呼吸道时受到动态调节，Arg1而不是PD-L1有助于CFPMN驱动的T细胞早期抑制，可能阻碍感染和炎症的消退。
Bacteria colonize cystic fibrosis (CF) airways, and while T cells with appropriate antigen specificity are present in draining lymph nodes, they are conspicuously absent from the lumen. To account for this absence, we hypothesized that polymorphonuclear neutrophils (PMNs), recruited massively into the CF airway lumen and actively exocytosing primary granules, also suppress T-cell function therein. Programmed Death-Ligand 1 (PD-L1), which exerts T-cell suppression at a late step, was expressed bimodally on CF airway PMNs, delineating PD-L1hi and PD-L1lo subsets, while healthy control (HC) airway PMNs were uniformly PD-L1hi. Blood PMNs incubated in CF airway fluid lost PD-L1 over time, and in coculture, antibody blockade of PD-L1 failed to inhibit the suppression of T-cell proliferation by CF airway PMNs. In contrast with PD-L1, arginase 1 (Arg1), which exerts T-cell suppression at an early step, was uniformly high on CF and HC airway PMNs. However, arginase activity was high in CF airway fluid and minimal in HC airway fluid, consistent with the fact that Arg1 activation requires primary granule exocytosis, which occurs in CF, but not HC, airway PMNs. In addition, Arg1 expression on CF airway PMNs correlated negatively with lung function and positively with arginase activity in CF airway fluid. Finally, combined treatment with arginase inhibitor and arginine rescued the suppression of T-cell proliferation by CF airway fluid. Thus, Arg1 and PD-L1 are dynamically modulated upon PMN migration into human airways, and, Arg1, but not PD-L1, contributes to early PMN-driven T-cell suppression in CF, likely hampering resolution of infection and inflammation.
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影响因子：
5.4
作者：
McNab, Finlay W.;Berry, Matthew P. R.;Graham, Christine M.;Bloch, Susannah A. A.;Oni, Tolu;Wilkinson, Katalin A.;Wilkinson, Robert J.;Kon, Onn M.;Banchereau, Jacques;Chaussabel, Damien;O'Garra, Anne
通讯作者：
O'Garra, Anne
DOI：
10.1146/annurev-pathol-020712-164023
发表时间：
2014
期刊：
Annual review of pathology
影响因子：
--
作者：
Mayadas TN;Cullere X;Lowell CA
通讯作者：
Lowell CA
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影响因子：
3.8
作者：
Chen, Yongjing;Wang, Qin;Zhang, Xueguang
通讯作者：
Zhang, Xueguang
影响因子：
20.3
作者：
Munder, M;Mollinedo, F;Modolell, M
通讯作者：
Modolell, M
影响因子：
4.4
作者：
Laval, Julie;Touhami, Jawida;Tirouvanziam, Rabindra
通讯作者：
Tirouvanziam, Rabindra