生物谷報(bào)道：加拿大麥克吉爾大學(xué) （McGill University’s）Ciriaco A. Piccirillo博士領(lǐng)導(dǎo)的一項(xiàng)研究發(fā)現(xiàn),，在一些人中，隨著年齡的增長(zhǎng),，特化的自體免疫調(diào)節(jié)T細(xì)胞逐漸失效,、變得更“懶惰”,，從而導(dǎo)致I型糖尿病的出現(xiàn)。該研究在基因工程構(gòu)建的非肥胖糖尿?。╪on-obese diabetic,，NOD）小鼠中進(jìn)行，結(jié)果發(fā)表在2008年1月的Diabetes上,。
在I型糖尿病中,，人體自身免疫系統(tǒng)的攻擊和破壞了胰島中的胰島β-細(xì)胞，使之不能產(chǎn)生胰島素,。如果不定期注射胰島素,，那么病人就可能發(fā)生糖尿病休克和死亡，也有可能發(fā)生許多次級(jí)的健康問(wèn)題（secondary health problems）包括失明,、心臟病和中風(fēng),。
Piccirillo博士說(shuō)，免疫系統(tǒng)為何會(huì)失去控制并破壞胰島,？其基因和細(xì)胞機(jī)理一直是個(gè)謎,，也是過(guò)去幾十年研究的熱門領(lǐng)域。過(guò)去幾年,，人們認(rèn)為喪失功能的調(diào)節(jié)性T細(xì)胞是該機(jī)制的關(guān)鍵因素,。我們的研究證實(shí)了這個(gè)觀點(diǎn)。
Piccirillo博士表示,，在小鼠和人類中,，F(xiàn)oxp3基因控制調(diào)節(jié)性CD4+T細(xì)胞的發(fā)育和功能，而調(diào)節(jié)性CD4+T細(xì)胞的主要作用是減輕炎癥反應(yīng),。微生物,、腫瘤、過(guò)敏原和移植組織這些物質(zhì)引起的各種免疫反應(yīng),，其功能受到調(diào)節(jié)性CD4+T細(xì)胞的抑制,。盡管糖尿病易感的NOD小鼠確實(shí)終生都能產(chǎn)生正常數(shù)量的Foxp3 T細(xì)胞，但Piccirillo及同事發(fā)現(xiàn),，隨著年齡的增長(zhǎng),，T細(xì)胞的功能不斷降低，使得胰島中的各種自身免疫反應(yīng)失去了控制,。
研究人員說(shuō),，在易感的個(gè)體身上，特定的易感基因,，與外在的環(huán)境因素和微生物感染共同作用,，很有可能改變了調(diào)節(jié)T細(xì)胞的功能，進(jìn)而引發(fā)胰島中全面的糖尿病自體免疫反應(yīng)。
Piccirillo博士說(shuō),，這些作用一旦開始,，這些免疫反應(yīng)就像不能剎車的小車滾下山坡一樣不受控制。此外,，他說(shuō),，這個(gè)研究不僅闡明了I型糖尿病觸發(fā)的機(jī)制，同時(shí)也給出了一個(gè)治療免疫系統(tǒng)相關(guān)疾病的治療方法,。
他說(shuō),，我們相信，這些調(diào)節(jié)性T細(xì)胞代表一類總開關(guān),，如果能理解它們是如何產(chǎn)生,、如何起作用以及如何生存的，我們將能夠從源頭阻止疾病的發(fā)生,。
生物谷推薦原始出處：
Diabetes Publish Ahead of Print published online ahead of print October 10, 2007
DOI: 10.2337/db06-1700
Published online October 10, 2007
Diabetes 57:113-123, 2008
DOI: 10.2337/db06-1700
Functional Waning of Naturally Occurring CD4+ Regulatory T-Cells Contributes to the Onset of Autoimmune Diabetes
Michael Tritt, Evridiki Sgouroudis, Eva d'Hennezel, Alexandre Albanese, and Ciriaco A. Piccirillo
From the Department of Microbiology and Immunology and McGill Center for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada
Address correspondence and reprint requests to Dr. Ciriaco A. Piccirillo, Department of Microbiology and Immunology, McGill University, 3775 University St., Room 510, Lyman Duff Medical Building, Montreal, QC, Canada H3A 2B4. E-mail: [email protected]
Key Words: APC, antigen-presenting cell • CFSE, carboxyfluorescein succinimidyl ester • FACS, fluorescence-activated cell sorter • HBSS, Hanks’ balanced salt solution • H-E, hematoxylin-eosin • IL, interleukin • IPEX, immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance • mAb, monoclonal antibody • nTreg, naturally occurring Foxp3+CD4+ regulatory T-cells • pancLN, pancreatic lymph node • Teff cell, effector T-cell • TNF-, tumor necrosis factor-
OBJECTIVE—In this study, we asked whether a possible quantitative or qualitative deficiency in naturally occurring Foxp3+CD4+ regulatory T-cells (nTreg), which display potent inhibitory effects on T-cell functions in vitro and in vivo, may predispose to the development of type 1 diabetes.
RESEARCH DESIGN AND METHODS—We assessed the frequency and function of Foxp3+ nTreg cells in primary and secondary lymphoid tissues in the NOD animal model of type 1 diabetes.
RESULTS—We show that the cellular frequency of Foxp3+ nTreg cells in primary and secondary lymphoid tissues is stable and does not decline relative to type 1 diabetes–resistant mice. We show that thymic and peripheral CD4+CD25+ T-cells are fully functional in vivo. We also examined the functional impact of CD4+Foxp3+ nTreg cells on the development of autoimmune diabetes, and we demonstrate that nTreg cells do not affect the initial priming or expansion of antigen-specific diabetogenic T-cells but impact their differentiation in pancreatic lymph nodes. Moreover, CD4+Foxp3+ nTreg cells also regulate later events of diabetogenesis by preferentially localizing in the pancreatic environment where they suppress the accumulation and function of effector T-cells. Finally, we show that the nTreg cell functional potency and intra-pancreatic proliferative potential declines with age, in turn augmenting diabetogenic responses and disease susceptibility.
CONCLUSIONS—This study demonstrates that Foxp3-expressing nTreg cells in NOD mice regulate diabetogenesis, but temporal alterations in nTreg cell function promote immune dysregulation and the onset of spontaneous autoimmunity.
