Mucosal Immunology Section, Oral Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Sci Transl Med. 2014 Jun 18;6(241):241ra78. doi: 10.1126/scitranslmed.3008895.
Harnessing regulatory T (Treg) cells is a promising approach for treating autoimmune disease. However, inducing antigen-specific Treg cells that target inflammatory immune cells without compromising beneficial immune responses has remained an unmet challenge. We developed a pathway to generate autoantigen-specific Treg cells in vivo, which showed therapeutic effects on experimental autoimmune encephalomyelitis and nonobese diabetes in mice. Specifically, we induced apoptosis of immune cells by systemic sublethal irradiation or depleted B and CD8(+) T cells with specific antibodies and then administered autoantigenic peptides in mice with established autoimmune diseases. We demonstrated mechanistically that apoptotic cells triggered professional phagocytes to produce transforming growth factor-β, under which the autoantigenic peptides directed naïve CD4(+) T cells to differentiate into Foxp3(+) Treg cells instead of into T effector cells in vivo. These antigen-specific Treg cells specifically ameliorated autoimmunity without compromising immune responses to bacterial antigen. We have thus successfully generated antigen-specific Treg cells with therapeutic activity toward autoimmunity. The findings may lead to the development of antigen-specific Treg cell-mediated immunotherapy for multiple sclerosis and type 1 diabetes and also other autoimmune diseases.
利用调节性 T（Treg）细胞是治疗自身免疫性疾病的一种有前途的方法。然而，诱导针对炎症性免疫细胞的抗原特异性 Treg 细胞而不损害有益的免疫反应仍然是一个未满足的挑战。我们开发了一种在体内产生自身抗原特异性 Treg 细胞的途径，该途径在实验性自身免疫性脑脊髓炎和非肥胖型糖尿病小鼠中显示出治疗效果。具体来说，我们通过全身亚致死辐射诱导免疫细胞凋亡，或用特异性抗体耗尽 B 和 CD8（+）T 细胞，然后在已建立自身免疫性疾病的小鼠中给予自身抗原肽。我们从机制上证明，凋亡细胞触发专业吞噬细胞产生转化生长因子-β，在这种情况下，自身抗原肽指导幼稚 CD4（+）T 细胞在体内分化为 Foxp3（+）Treg 细胞，而不是 T 效应细胞。这些抗原特异性 Treg 细胞特异性地改善了自身免疫而不损害对细菌抗原的免疫反应。因此，我们成功地产生了具有针对自身免疫的治疗活性的抗原特异性 Treg 细胞。这些发现可能会导致针对多发性硬化症和 1 型糖尿病以及其他自身免疫性疾病的抗原特异性 Treg 细胞介导的免疫疗法的发展。
