Insufficient interleukin-12 signalling favours differentiation of human CD4+ and CD8+ T cells into GATA-3+ and GATA-3+ T-bet+ subsets in humanized mice
Insufficient interleukin-12 signalling favours differentiation of human CD4+ and CD8+ T cells into GATA-3+ and GATA-3+ T-bet+ subsets in humanized mice
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DOI：
10.1111/imm.12304
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发表时间：
2014-10-01
期刊：
影响因子：
6.4
通讯作者：
Ploss, Alexander
中科院分区：
文献类型：
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作者：
Billerbeck, Eva;Labitt, Rachael N.;Ploss, Alexander
CD 4（+）T细胞分化为1型或2型亚群是由相反谱系定义转录因子T-bet和加塔-3的表达介导的。然而，小鼠中加塔-3（+）T-bet（+）CD 4（+）T细胞的存在表明这些亚群的功能可塑性。关于体内人类T细胞亚群的1型和2型可塑性知之甚少。在这里，我们发现在缺乏功能性免疫调节网络的人源化小鼠的异种环境中，人CD 4（+），特别是CD 8（+）T细胞优先分化为白细胞介素（IL）-4（+）加塔-3（+）和IL-4（+）干扰素-γ（+）加塔-3（+）T-bet（+）亚群。用重组人IL-12处理或在体内扩增产生IL-12的人树突状细胞可逆转该表型，并导致加塔-3表达下调。这些变化也与人源化小鼠中改善的抗病毒免疫应答相关。总之，我们的研究显示了人CD 4（+）和CD 8（+）T细胞在人源化小鼠中稳定共表达加塔-3和T-bet的能力，并揭示了IL-12在调节该表型中的关键作用。
Differentiation of CD4(+) T cells into type 1 or type 2 subsets is mediated by the expression of the opposing lineage defining transcription factors T-bet and GATA-3. However, the existence of GATA-3(+) T-bet(+) CD4(+) T cells in mice suggests functional plasticity of these subsets. Little is known about type 1 and type 2 plasticity of human T-cell subsets in vivo. Here, we show that in the xenogeneic environment of humanized mice, which lacks a functional immune-regulatory network, human CD4(+) and, notably, CD8(+) T cells preferentially differentiate into interleukin (IL)-4(+) GATA-3(+) and IL-4(+) interferon-gamma(+) GATA-3(+) T-bet(+) subsets. Treatment with recombinant human IL-12 or expansion of IL-12-producing human dendritic cells in vivo reverted this phenotype and led to the down-regulation of GATA-3 expression. These changes also correlated with improved antiviral immune responses in humanized mice. In conclusion, our study shows the capacity of human CD4(+) and CD8(+) T cells for stable co-expression of GATA-3 and T-bet in humanized mice and reveals a critical role for IL-12 in regulating this phenotype.