來自美國圣·猶大兒童研究醫(yī)院發(fā)現(xiàn)了一個(gè)新的信號(hào)分子,，該分子能夠抑制損傷身體的免疫應(yīng)答,。這一發(fā)現(xiàn)將能夠有助于研究人員開發(fā)出癌癥新疫苗,、免疫疾?。ㄈ鏘型糖尿?。┖脱装Y（如腸炎和哮喘）的新療法,。
圣·猶大的研究組發(fā)現(xiàn)，特化的免疫淋巴細(xì)胞——調(diào)節(jié)性T細(xì)胞釋放一種由兩個(gè)叫做Ebi3和Il12a的蛋白質(zhì)構(gòu)成的蛋白質(zhì)復(fù)合體,。這種蛋白質(zhì)復(fù)合體如同效應(yīng)器T淋巴細(xì)胞活性的一個(gè)“剎車”,。這項(xiàng)研究的結(jié)果發(fā)表在11月22日的《自然》雜志上。
這種新的蛋白質(zhì)復(fù)合體是一大類叫做細(xì)胞激素的信號(hào)分子中的一員,。,，細(xì)胞激素能夠告訴細(xì)胞與其他細(xì)胞進(jìn)行交流。由于免疫系統(tǒng)細(xì)胞激素白介素,，因此該研究組將這種蛋白命名為白介素－35(IL-35),。大多數(shù)細(xì)胞激素通過驅(qū)動(dòng)免疫攻擊或?qū)е卵装Y來次級(jí)免疫系統(tǒng)細(xì)胞。但是,，IL-35則是少數(shù)的能抑制免疫系統(tǒng)活性的信號(hào)分子。
研究人員表示,，IL-35的發(fā)現(xiàn)具有非常重要的意義,，因?yàn)閷?duì)調(diào)節(jié)型T細(xì)胞的操作是免疫治療的一個(gè)重要目標(biāo)。免疫療法是一種通過操作免疫系統(tǒng)來增強(qiáng)或抑制其活性進(jìn)而治療感染,、癌癥或其他疾病的方法,。盡管調(diào)節(jié)型T細(xì)胞介導(dǎo)的免疫療法對(duì)具有很大的治療潛力，但是負(fù)責(zé)細(xì)胞抑制免疫系統(tǒng)活性能力的分子卻知之甚少,，而這個(gè)問題也是阻礙該領(lǐng)域發(fā)展的一個(gè)重要問題,。
原始出處:
Nature 450, 566-569 (22 November 2007) | doi:10.1038/nature06306; Received 31 July 2007; Accepted 26 September 2007
The inhibitory cytokine IL-35 contributes to regulatory T-cell function
Lauren W. Collison1, Creg J. Workman1, Timothy T. Kuo3, Kelli Boyd2, Yao Wang1, Kate M. Vignali1, Richard Cross1, David Sehy4, Richard S. Blumberg3 & Dario A. A. Vignali1
Department of Immunology,
Animal Resources Center, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
eBioscience, San Diego, California 92121, USA
Correspondence to: Dario A. A. Vignali1 Correspondence and requests for materials should be addressed to D.A.A.V. (Email: [email protected]).
Regulatory T (Treg) cells are a critical sub-population of CD4+ T cells that are essential for maintaining self tolerance and preventing autoimmunity1, 2, for limiting chronic inflammatory diseases, such as asthma and inflammatory bowel disease3, 4, and for regulating homeostatic lymphocyte expansion5. However, they also suppress natural immune responses to parasites6 and viruses7 as well as anti-tumour immunity induced by therapeutic vaccines8. Although the manipulation of Treg function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. Here we demonstrate that Epstein-Barr-virus-induced gene 3 (Ebi3, which encodes IL-27) and interleukin-12 alpha (Il12a, which encodes IL-12/p35) are highly expressed by mouse Foxp3+ (forkhead box P3) Treg cells but not by resting or activated effector CD4+ T (Teff) cells, and that an Ebi3–IL-12 heterodimer is constitutively secreted by Treg but not Teff cells. Both Ebi3 and Il12a messenger RNA are markedly upregulated in Treg cells co-cultured with Teff cells, thereby boosting Ebi3 and IL-12 production in trans. Treg-cell restriction of this cytokine occurs because Ebi3 is a downstream target of Foxp3, a transcription factor that is required for Treg-cell development and function. Ebi3 –/– and Il12a –/– Treg cells have significantly reduced regulatory activity in vitro and fail to control homeostatic proliferation and to cure inflammatory bowel disease in vivo. Because these phenotypic characteristics are distinct from those of other IL-12 family members, this novel Ebi3–IL-12 heterodimeric cytokine has been designated interleukin-35 (IL-35). Ectopic expression of IL-35 confers regulatory activity on naive T cells, whereas recombinant IL-35 suppresses T-cell proliferation. Taken together, these data identify IL-35 as a novel inhibitory cytokine that may be specifically produced by Treg cells and is required for maximal suppressive activity.
