生物谷报道：加拿大麦克吉尔大学 （McGill University’s）Ciriaco A. Piccirillo博士领导的一项研究发现，在一些人中，随着年龄的增长，特化的自体免疫调节T细胞逐渐失效、变得更“懒惰”，从而导致I型糖尿病的出现。该研究在基因工程构建的非肥胖糖尿病（non-obese diabetic，NOD）小鼠中进行，结果发表在2008年1月的Diabetes上。
在I型糖尿病中，人体自身免疫系统的攻击和破坏了胰岛中的胰岛β-细胞，使之不能产生胰岛素。如果不定期注射胰岛素，那么病人就可能发生糖尿病休克和死亡，也有可能发生许多次级的健康问题（secondary health problems）包括失明、心脏病和中风。
Piccirillo博士说，免疫系统为何会失去控制并破坏胰岛？其基因和细胞机理一直是个谜，也是过去几十年研究的热门领域。过去几年，人们认为丧失功能的调节性T细胞是该机制的关键因素。我们的研究证实了这个观点。
Piccirillo博士表示，在小鼠和人类中，Foxp3基因控制调节性CD4+T细胞的发育和功能，而调节性CD4+T细胞的主要作用是减轻炎症反应。微生物、肿瘤、过敏原和移植组织这些物质引起的各种免疫反应，其功能受到调节性CD4+T细胞的抑制。尽管糖尿病易感的NOD小鼠确实终生都能产生正常数量的Foxp3 T细胞，但Piccirillo及同事发现，随着年龄的增长，T细胞的功能不断降低，使得胰岛中的各种自身免疫反应失去了控制。
研究人员说，在易感的个体身上，特定的易感基因，与外在的环境因素和微生物感染共同作用，很有可能改变了调节T细胞的功能，进而引发胰岛中全面的糖尿病自体免疫反应。
Piccirillo博士说，这些作用一旦开始，这些免疫反应就像不能刹车的小车滚下山坡一样不受控制。此外，他说，这个研究不仅阐明了I型糖尿病触发的机制，同时也给出了一个治疗免疫系统相关疾病的治疗方法。
他说，我们相信，这些调节性T细胞代表一类总开关，如果能理解它们是如何产生、如何起作用以及如何生存的，我们将能够从源头阻止疾病的发生。
生物谷推荐原始出处：
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: ciro.piccirillo@mcgill.ca
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.
