Blood：肿瘤抑制因子调节了树突细胞的分化与成熟

近日，来自美国乔治城大学医学中心的研究人员发现，肿瘤抑制因子p15Ink4b调节了传统树突细胞的分化与成熟。相关研究成果于5月24日发表在Blood上。

p15INK4B基因是近年来发现的细胞周期蛋白依赖性激酶抑制因子(CKI)家族中的一个新成员，能抑制多种肿瘤细胞的增殖。研究发现，在急性髓细胞性白血病及其它的髓系疾病，肿瘤抑制因子p15Ink4b频繁的被甲基化而失活。

树突细胞(DCs)作为有效的APCs（抗原提呈细胞），在抗白血病免疫反应中起着至关重要的调节作用。研究发现，在树突细胞的分化以及激活期间，p15Ink4b的表达被强烈的诱导，而它的失去却显著的影响了传统树突细胞(cDC)的发育。而且，p15Ink4b敲除小鼠体内的传统树突细胞，其抗原呈递 (MHC II)以及共刺激(CD80和CD86)分子的表达显著的降低，导致它的免疫刺激功能（包括抗原摄入及T细胞激活）受损。

在祖细胞内，重新表达p15Ink4b能够恢复这些功能，这表明，p15Ink4b对cDC的分化及成熟起到了积极的作用。

PU.1转录因子是保守的DNA结合蛋白Ets家族成员，主要在造血系统如髓细胞和B淋巴细胞中表达，并调节关键髓系基因的转录从而调控造血系统的分化。在这项研究里，他们还发现，p15Ink4b的表达能够提高Erk1/Erk2激酶的磷酸化，导致PU.1转录因子的活性增加。

总的来说，该研究表明p15Ink4b是树突细胞发育的一个重要调节因子，阐明了该肿瘤抑制因子在调节适应性免疫应答中新的功能。

doi: 10.1182/blood-2011-10-387613
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The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells

Joanna Fares, Richard Koller, Rita Humeniuk, Linda Wolff, and Juraj Bies.

The tumor suppressor p15Ink4b is frequently inactivated by methylation in acute myeloid leukemia and premalignant myeloid disorders. Dendritic cells (DCs) as potent APCs play critical regulatory roles in antileukemic immune responses. In the present study, we investigated whether p15Ink4b can function as modulator of DC development.The expression of p15Ink4b is induced strongly during differentiation and activation of DCs, and its loss resulted in significant quantitative and qualitative impairments of conventional DC (cDC) development. Accordingly, ex vivo–generated BM-derived DCs from p15Ink4b-knockout mice express significantly decreased levels of the antigen-presenting (MHC II) and costimulatory (CD80 and CD86) molecules and have impaired immunostimulatory functions, such as antigen uptake and T-cell stimulation.Reexpression of p15Ink4b in progenitors restored these defects, and confirmed a positive role for p15Ink4b during cDC differentiation and maturation. Furthermore, we have shown herein that p15Ink4b expression increases phosphorylation of Erk1/Erk2 kinases, which leads to an elevated activity of the PU.1 transcription factor. In conclusion, our results establish p15Ink4b as an important modulator of cDC development and implicate a novel function for this tumor suppressor in the regulation of adaptive immune responses.