Comparison of primary human cytotoxic T-cell and natural killer cell responses reveal similar molecular requirements for lytic granule exocytosis but differences in cytokine production
Comparison of primary human cytotoxic T-cell and natural killer cell responses reveal similar molecular requirements for lytic granule exocytosis but differences in cytokine production
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DOI：
10.1182/blood-2012-07-442558
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发表时间：
2013-02-21
期刊：
影响因子：
20.3
通讯作者：
Bryceson, Yenan T.
中科院分区：
文献类型：
--
作者：
Chiang, Samuel C. C.;Theorell, Jakob;Bryceson, Yenan T.
细胞毒性淋巴细胞，包括细胞毒性T淋巴细胞(CTL)和自然杀伤(NK)细胞，通过释放含有穿孔素的裂解颗粒杀死病原体感染的、肿瘤的或某些造血细胞。在本研究中，我们首先对CD8(+)T细胞上的分化和裂解颗粒标记进行了概率状态建模，以便能够比较真实的CTL和NK细胞。分析证实CD57(Bright)表达是含有颗粒标记的CTL的可靠表型。然后，我们比较了CD3(+)、CD8(+)、CD57(明亮)CTL和NK细胞。健康成人外周血CD3(+)、CD8(+)、CD57(明亮)CTL较CD3(-)、CD56(Dim)NK细胞表达更多的颗粒酶B而较少的穿孔素。在刺激下，这种CTL比其他T细胞亚群更容易脱颗粒，但有类似于NK细胞的脱颗粒倾向。值得注意的是，CTL比NK细胞更快、更频繁地产生细胞因子。在与家族性噬血细胞淋巴组织细胞增多症相关的UNC13D、STX11或STXBP2双等位基因突变的患者中，CTL和NK细胞脱颗粒也同样受损。因此，细胞毒性淋巴细胞亚群在溶血颗粒胞吐中对Munc13-4、Synaxin-11和Munc18-2有相似的要求。本研究结果提供了人类CD3(+)、CD8(+)、CD57(Bright)CTL和NK细胞的详细比较，提示CD57(Bright)CTL功能的分析可能有助于包括家族性噬血细胞淋巴组织细胞增多症在内的原发免疫缺陷的诊断。
Cytotoxic lymphocytes, encompassing cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, kill pathogen-infected, neoplastic, or certain hematopoietic cells through the release of perforin-containing lytic granules. In the present study, we first performed probability-state modeling of differentiation and lytic granule markers on CD8(+) T cells to enable the comparison of bona fide CTLs with NK cells. Analysis identified CD57(bright) expression as a reliable phenotype of granule marker-containing CTLs. We then compared CD3(+)CD8(+)CD57(bright) CTLs with NK cells. Healthy adult peripheral blood CD3(+)CD8(+)CD57(bright) CTLs expressed more granzyme B but less perforin than CD3(-)CD56(dim) NK cells. On stimulation, such CTLs degranulated more readily than other T-cell subsets, but had a propensity to degranulate that was similar to NK cells. Remarkably, the CTLs produced cytokines more rapidly and with greater frequency than NK cells. In patients with biallelic mutations in UNC13D, STX11, or STXBP2 associated with familial hemophagocytic lymphohistiocytosis, CTL and NK cell degranulation were similarly impaired. Therefore, cytotoxic lymphocyte subsets have similar requirements for Munc13-4, syntaxin-11, and Munc18-2 in lytic granule exocytosis. The present results provide a detailed comparison of human CD3(+)CD8(+)CD57(bright) CTLs and NK cells and suggest that analysis of CD57(bright) CTL function may prove useful in the diagnosis of primary immunodeficiencies including familial hemophagocytic lymphohistiocytosis.