Reversal of Autoimmunity by Boosting Memory-like Autoregulatory T Cells

被引:246
作者
Tsai, Sue [1 ,2 ]
Shameli, Afshin [1 ,2 ]
Yamanouchi, Jun [1 ,2 ]
Clemente-Casares, Xavier [1 ,2 ]
Wang, Jinguo [1 ,2 ]
Serra, Pau [1 ,2 ]
Yang, Yang [1 ,2 ,3 ]
Medarova, Zdravka [4 ]
Moore, Anna [4 ]
Santamaria, Pere [1 ,2 ]
机构
[1] Univ Calgary, Dept Microbiol & Infect Dis, Julia McFarlane Diabet Res Ctr, Calgary, AB T2N 4N1, Canada
[2] Univ Calgary, Inst Inflammat Infect & Immun, Calgary, AB T2N 4N1, Canada
[3] Univ Calgary, Fac Med, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada
[4] Massachusetts Gen Hosp, Dept Radiol, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Mol Imaging Lab, Charlestown, MA 02129 USA
基金
加拿大健康研究院; 加拿大自然科学与工程研究理事会;
关键词
NONOBESE DIABETIC MICE; AVIDITY MATURATION; NOD MICE; EFFECTOR; POPULATION; TOLERANCE; RESPONSES; ANTIGENS;
D O I
10.1016/j.immuni.2010.03.015
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Blunting autoreactivity without compromising immunity remains an elusive goal in the treatment of autoimmunity. We show that progression to autoimmune diabetes results in the conversion of naive low-avidity autoreactive CD8(+) T cells into memory-like autoregulatory cells that can be expanded in vivo with nanoparticles coated with disease-relevant peptide-major histocompatibility complexes (pMHC-NP). Treatment of NOD mice with monospecific pMHC-NPs expanded cognate autoregulatory T cells, suppressed the recruitment of noncognate specificities, prevented disease in prediabetic mice, and restored normoglycemia in diabetic animals. pMHC-NP therapy was inconsequential in mice engineered to bear an immune system unresponsive to the corresponding epitope, owing to absence of epitope-experienced autoregulatory T cells. pMHC-NP-expanded autoregulatory T cells suppressed local presentation of autoantigens in an interferon-gamma-, indoleamine 2,3-dioxygenase-, and perforin-dependent manner. Nanoparticles coated with human diabetes-relevant pHLA complexes restored normoglycemia in a humanized model of diabetes. These observations expose a paradigm in the pathogenesis of autoimmunity amenable for therapeutic intervention.
引用
收藏
页码:568 / 580
页数:13
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