Tian Jide, Zekzer Dan, Lu Yuxin, Dang Hoa, Kaufman Daniel L
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, 90095, USA.
J Immunol. 2006 Feb 15;176(4):2654-61. doi: 10.4049/jimmunol.176.4.2654.
The determinant spreading of T cell autoimmunity plays an important role in the pathogenesis of type 1 diabetes and in the protective mechanism of Ag-based immunotherapy in NOD mice. However, little is known about the role of APCs, particularly B cells, in the spreading of T cell autoimmunity. We studied determinant spreading in NOD/scid or Igmu(-/-) NOD mice reconstituted with NOD T and/or B cells and found that mice with mature B cells (TB NOD/scid and BMB Igmu(-/-) NOD), but not mice that lacked mature B cells (T NOD/scid and BM Igmu(-/-) NOD), spontaneously developed Th1 autoimmunity, which spread sequentially among different beta cell Ags. Immunization of T NOD/scid and BM Igmu(-/-) NOD mice with a beta cell Ag could prime Ag-specific Th1 or Th2 responses, but those T cell responses did not spread to other beta cell Ags. In contrast, immunization of TB NOD/scid and BMB Igmu(-/-) NOD mice with a beta cell Ag in IFA induced Th2 responses, which spread to other beta cell Ags. Furthermore, we found that while macrophages and dendritic cells could evoke memory and effector T cell responses in vitro, B cells significantly enhanced the detection of spontaneously primed and induced Th1 responses to beta cell Ags. Our data suggest that B cells, but not other APCs, mediate the spreading of T cell responses during the type 1 diabetes process and following Ag-based immunotherapy. Conceivably, the modulation of the capacity of B cells to present Ag may provide new interventions for enhancing Ag-based immunotherapy and controlling autoimmune diseases.
T细胞自身免疫的决定性扩展在1型糖尿病的发病机制以及NOD小鼠基于抗原的免疫治疗的保护机制中发挥着重要作用。然而，关于抗原呈递细胞（APCs），尤其是B细胞，在T细胞自身免疫扩展中的作用，人们知之甚少。我们研究了用NOD T细胞和/或B细胞重建的NOD/scid或Igmu(-/-) NOD小鼠中的决定性扩展，发现具有成熟B细胞的小鼠（TB NOD/scid和BMB Igmu(-/-) NOD），而非缺乏成熟B细胞的小鼠（T NOD/scid和BM Igmu(-/-) NOD），会自发产生Th1自身免疫，这种自身免疫会在不同的β细胞抗原之间依次扩散。用一种β细胞抗原免疫T NOD/scid和BM Igmu(-/-) NOD小鼠可引发抗原特异性Th1或Th2反应，但这些T细胞反应不会扩散到其他β细胞抗原。相反，用IFA中的一种β细胞抗原免疫TB NOD/scid和BMB Igmu(-/-) NOD小鼠会诱导Th2反应，该反应会扩散到其他β细胞抗原。此外，我们发现虽然巨噬细胞和树突状细胞可在体外引发记忆和效应T细胞反应，但B细胞能显著增强对β细胞抗原自发引发和诱导的Th1反应的检测。我们的数据表明，在1型糖尿病过程中以及基于抗原的免疫治疗后，介导T细胞反应扩散的是B细胞，而非其他抗原呈递细胞。可以想象，调节B细胞呈递抗原的能力可能为增强基于抗原的免疫治疗和控制自身免疫性疾病提供新的干预措施。
