Phenotypic and transcriptional profile correlates with functional plasticity of antigen-specific CD4+ T cells
Phenotypic and transcriptional profile correlates with functional plasticity of antigen-specific CD4+ T cells
复制标题
DOI：
10.1038/icb.2013.88
复制
发表时间：
2014-02-01
影响因子：
4
通讯作者：
Khanna, Rajiv
中科院分区：
文献类型：
--
作者：
Edwards, Emily S. J.;Smith, Corey;Khanna, Rajiv
CD4(+)T细胞在控制感染性病原体中的作用是高度复杂的，具有多种功能，但这些T细胞如何获得不同的功能潜力仍未明确。在这里，我们发现针对不同病毒抗原的人类巨细胞病毒(CMV)特异性CD4(+)T细胞主要表达单独的肿瘤坏死因子-α或肿瘤坏死因子-α和干扰素-γc。肿瘤坏死因子-α(+)和干扰素-γ(+)的CD4(+)T细胞表达显著更高水平的T-box转录因子T-bet并伴有Eomesodermin(EOMS)表达的渐进性丧失(T-bet(Hi)Eome(Hi/Lo))，与表达较低水平的T-bet和Eome(T-bet(Hi)Eome(-))的TNF-α(+)CD4+T细胞相比。此外，肿瘤坏死因子-α(+)和干扰素-γ(+)的CD4(+)T细胞表达较高水平的穿孔素和白介素2，并表现为终末分化表型(CCR7(-)CD27(-)CD45RA(-)CD57(+)CD62L(-))。相反，单独的肿瘤坏死因子-α(+)CMV特异性的CD4+T细胞主要是早期记忆表型，其中一部分细胞表现为T记忆干细胞表型(CD95(+)CD45RA(+)CCR7(+)CD27(+))。在IL-12存在的情况下，用病毒抗原体外刺激CMV特异性的CD4(+)T细胞足以显著改变肿瘤坏死因子-α(+)CD4(+)T细胞的转录和功能，而肿瘤坏死因子-α(+)和干扰素-γ(+)CD4(+)T细胞保持不变。这些发现说明了细胞因子表达、转录调控和细胞分化之间的内在联系，以及它们对病毒特异性CD4(+)T细胞功能可塑性的影响。
The role of CD4(+) T cells in the control of infectious pathogens is highly complex with a myriad of functions but how these T cells acquire differential functional potentiality remains poorly defined. Here we show that human cytomegalovirus (CMV)specific CD4(+) T cells directed towards different viral antigens expressed predominantly TNF-alpha alone or TNF-alpha a and IFN-gamma c. TNF-alpha(+) and IFN-gamma(+) CD4(+) T cells expressed significantly higher levels of T-box transcription factors T-bet with graded loss of Eomesodermin (Eomes) expression (T-bet(Hi)Eomes(Hi/ Lo)) when compared with TNF-alpha(+) CD4+ T cells expressing lower levels of both T-bet and Eomes (T-bet(Hi)Eomes(-)). Furthermore, TNF-alpha(+) and IFN-gamma(+) CD4(+) T cells expressed significantly higher levels of perforin and interleukin (IL)-2 and displayed a terminally differentiated phenotype (CCR7(-)CD27(-)CD45RA(-)CD57(+)CD62L(-)). In contrast, TNF-alpha(+) alone CMV-specific CD4+ T cells were predominantly early-memory phenotype with a proportion of these cells displaying T memory stem-cell phenotype (CD95(+)CD45RA(+)CCR7(+)CD27(+)). In vitro stimulation of CMV-specific CD4(+) T cells with viral antigen in the presence of IL-12 was sufficient to dramatically change the transcriptional and functional profile of TNF-alpha(+) CD4(+) T cells, whereas TNF-alpha(+) and IFN-gamma(+) CD4(+) T cells remained unaltered. These findings illustrate an intrinsic link between cytokine expression, transcriptional regulation and cellular differentiation, and their impact on functional plasticity of virus-specific CD4(+) T cells.