Inserm, Unit 1020, Medical Faculty Déscartes, Paris, France.
Blood. 2012 May 24;119(21):4928-38. doi: 10.1182/blood-2011-12-395186. Epub 2012 Apr 6.
CD8 T cells lose the capacity to control HIV infection, but the extent of the impairment of CD8 T-cell functions and the mechanisms that underlie it remain controversial. Here we report an extensive ex vivo analysis of HIV-specific CD8 T cells, covering the expression of 16 different molecules involved in CD8 function or differentiation. This approach gave remarkably homogeneous readouts in different donors and showed that CD8 dysfunction in chronic HIV infection was much more severe than described previously: some Ifng transcription was observed, but most cells lost the expression of all cytolytic molecules and Eomesodermin and T-bet by chronic infection. These results reveal a cellular mechanism explaining the dysfunction of CD8 T cells during chronic HIV infection, as CD8 T cells are known to maintain some functionality when either of these transcription factors is present, but to lose all cytotoxic activity when both are not expressed. Surprisingly, they also show that chronic HIV and lymphocytic choriomeningitis virus infections have a very different impact on fundamental T-cell functions, "exhausted" lymphocytic choriomeningitis virus-specific cells losing the capacity to secrete IFN-γ but maintaining some cytotoxic activity as granzyme B and FasL are overexpressed and, while down-regulating T-bet, up-regulating Eomesodermin expression.
CD8 T 细胞失去了控制 HIV 感染的能力，但 CD8 T 细胞功能受损的程度及其潜在机制仍存在争议。在这里，我们报告了一项对 HIV 特异性 CD8 T 细胞的广泛体外分析，涵盖了涉及 CD8 功能或分化的 16 种不同分子的表达。这种方法在不同供体中给出了非常一致的结果，并表明慢性 HIV 感染中的 CD8 功能障碍比以前描述的更为严重：虽然观察到一些 Ifng 转录，但大多数细胞在慢性感染过程中丧失了所有细胞毒性分子和 Eomesodermin 和 T-bet 的表达。这些结果揭示了一种细胞机制，解释了慢性 HIV 感染期间 CD8 T 细胞的功能障碍，因为当存在这些转录因子中的任何一个时，CD8 T 细胞被认为保持一定的功能，但当两者都不表达时，会丧失所有细胞毒性活性。令人惊讶的是，它们还表明慢性 HIV 和淋巴细胞性脉络丛脑膜炎病毒感染对基本 T 细胞功能有非常不同的影响，“耗竭”的淋巴细胞性脉络丛脑膜炎病毒特异性细胞丧失了分泌 IFN-γ 的能力，但由于颗粒酶 B 和 FasL 的过度表达，保持了一些细胞毒性活性，同时下调 T-bet，上调 Eomesodermin 的表达。
