Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
J Immunol. 2011 Sep 1;187(5):2656-65. doi: 10.4049/jimmunol.1002928. Epub 2011 Jul 29.
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects several million people in Latin America. Myocarditis, observed in the acute and chronic phases of the disease, is characterized by a mononuclear cell inflammatory infiltrate. We previously identified a myeloid cell population in the inflammatory heart infiltrate of infected mice that expressed arginase I. In this study, we purified CD11b(+) myeloid cells from the heart and analyzed their phenotype and function. Those CD11b(+) cells were ∼70% Ly6G(-)Ly6C(+) and 25% Ly6G(+)Ly6C(+). Moreover, purified CD11b(+)Ly6G(-) cells, but not Ly6G(+) cells, showed a predominant monocytic phenotype, expressed arginase I and inducible NO synthase, and suppressed anti-CD3/anti-CD28 Ab-induced T cell proliferation in vitro by an NO-dependent mechanism, activity that best defines myeloid-derived suppressor cells (MDSCs). Contrarily, CD11b(+)Ly6G(+) cells, but not CD11b(+)Ly6G(-) cells, expressed S100A8 and S100A9, proteins known to promote recruitment and differentiation of MDSCs. Together, our results suggest that inducible NO synthase/arginase I-expressing CD11b(+)Ly6G(-) myeloid cells in the hearts of T. cruzi-infected mice are MDSCs. Finally, we found plasma l-arginine depletion in the acute phase of infection that was coincident in time with the appearance of MDSCs, suggesting that in vivo arginase I could be contributing to l-arginine depletion and systemic immunosuppression. Notably, l-arginine supplementation decreased heart tissue parasite load, suggesting that sustained arginase expression through the acute infection is detrimental for the host. This is, to our knowledge, the first time that MDSCs have been found in the heart in the context of myocarditis and also in infection by T. cruzi.
克氏锥虫引起的恰加斯病影响了拉丁美洲数百万人。在疾病的急性和慢性阶段观察到心肌炎，其特征是单核细胞炎症浸润。我们之前在感染小鼠的炎症性心脏浸润中鉴定出一种表达精氨酸酶 I 的髓样细胞群体。在这项研究中，我们从心脏中纯化了 CD11b(+)髓样细胞，并分析了它们的表型和功能。那些 CD11b(+)细胞约为 70%Ly6G(-)Ly6C(+)和 25%Ly6G(+)Ly6C(+)。此外，纯化的 CD11b(+)Ly6G(-)细胞，但不是 Ly6G(+)细胞，表现出主要的单核细胞表型，表达精氨酸酶 I 和诱导型一氧化氮合酶，并通过依赖 NO 的机制体外抑制抗-CD3/抗-CD28 Ab 诱导的 T 细胞增殖，这种活性最能定义髓源性抑制细胞 (MDSCs)。相反，CD11b(+)Ly6G(+)细胞，但不是 CD11b(+)Ly6G(-)细胞，表达 S100A8 和 S100A9，这两种蛋白已知可促进 MDSCs 的募集和分化。总之，我们的结果表明，在 T. cruzi 感染小鼠的心脏中，诱导型一氧化氮合酶/精氨酸酶 I 表达的 CD11b(+)Ly6G(-)髓样细胞是 MDSCs。最后，我们发现感染急性期血浆 l-精氨酸耗竭与 MDSCs 的出现时间一致，提示体内精氨酸酶 I 可能导致 l-精氨酸耗竭和全身免疫抑制。值得注意的是，l-精氨酸补充降低了心脏组织中的寄生虫载量，这表明急性感染期间持续表达精氨酸酶对宿主是有害的。据我们所知，这是首次在心肌炎和 T. cruzi 感染的情况下在心脏中发现 MDSCs。
