Makarenkova Valeriya P, Bansal Vishal, Matta Benjamin M, Perez Lori Ann, Ochoa Juan B
Department of Surgery, University of Pittsburgh Medical Center, PA 15213, USA.
J Immunol. 2006 Feb 15;176(4):2085-94. doi: 10.4049/jimmunol.176.4.2085.
T cell dysfunction that occurs after surgery or trauma is associated with a poor clinical outcome. We describe that myeloid suppressor cells expressing CD11b(+)/Gr-1(+) markers invade the spleen after traumatic stress and suppress T cell function through the production of arginase 1. We created a consistent model of traumatic stress in C57BL/6 mice to perform this work. A significant number of CD11b(+)/Gr-1(+) cells expressing arginase 1 accumulated in T cell zones around the germinal centers of the white pulp of the spleen within 6 h of trauma and lasted for at least 72 h. Increased arginase activity and arginase 1 expression, along with increased [(3)H]arginine uptake, l-arginine depletion, and l-ornithine accumulation in the culture medium, were observed exclusively in CD11b(+)/Gr-1(+) cells after traumatic stress. Flow cytometry revealed CD11b(+)/Gr-1(+) as a heterogeneous myeloid suppressor cell also expressing low levels of MHC class I and II, CD80, CD86, CD31, and others. When compared with controls, trauma-induced CD11b(+)/Gr-1(+) cells significantly inhibited CD3/CD28-mediated T cell proliferation, TCR zeta-chain expression, and IL-2 production. The suppressive effects by trauma CD11b(+)/Gr-1(+) cells were overcome with the arginase antagonist N-hydroxy-nor-l-arginine or extrasupplementation of medium with l-arginine. Poor Ag-presenting capacity of control and trauma-induced CD11b(+)/Gr-1(+) cells was detected in allogeneic murine leukocyte reaction. This study demonstrates that CD11b(+)/Gr-1(+) cells invade the spleen following traumatic stress and cause T cell dysfunction by an arginase-mediated mechanism, probably that of arginine depletion. Understanding the mechanism of immune suppression by these cells has important clinical implications in the treatment of immune dysfunction after trauma or surgery.
手术或创伤后发生的T细胞功能障碍与不良临床结局相关。我们描述了表达CD11b(+)/Gr-1(+)标志物的髓样抑制细胞在创伤应激后侵入脾脏，并通过产生精氨酸酶1抑制T细胞功能。我们在C57BL/6小鼠中建立了一个一致的创伤应激模型来开展这项研究。创伤后6小时内，大量表达精氨酸酶1的CD11b(+)/Gr-1(+)细胞积聚在脾脏白髓生发中心周围的T细胞区，并持续至少72小时。创伤应激后，仅在CD11b(+)/Gr-1(+)细胞中观察到精氨酸酶活性和精氨酸酶1表达增加，同时培养基中[(3)H]精氨酸摄取增加、L-精氨酸耗竭和L-鸟氨酸积累。流式细胞术显示CD11b(+)/Gr-1(+)是一种异质性髓样抑制细胞，也低水平表达MHC I类和II类、CD80、CD86、CD31等。与对照组相比，创伤诱导的CD11b(+)/Gr-1(+)细胞显著抑制CD3/CD28介导的T细胞增殖、TCR ζ链表达和IL-2产生。创伤CD11b(+)/Gr-1(+)细胞的抑制作用可被精氨酸酶拮抗剂N-羟基-nor-L-精氨酸或向培养基中额外补充L-精氨酸所克服。在同种异体小鼠白细胞反应中检测到对照组和创伤诱导的CD11b(+)/Gr-1(+)细胞的抗原呈递能力较差。本研究表明，CD11b(+)/Gr-1(+)细胞在创伤应激后侵入脾脏，并通过精氨酸酶介导的机制（可能是精氨酸耗竭机制）导致T细胞功能障碍。了解这些细胞的免疫抑制机制对创伤或手术后免疫功能障碍的治疗具有重要的临床意义。
