Scheuplein Felix, Lamont Deanna J, Poynter Matthew E, Boyson Jonathan E, Serreze David, Lundblad Lennart K A, Mashal Robert, Schaub Robert
NKT Therapeutics, Inc., Waltham, MA, United States of America.
The Jackson Laboratory, Bar Harbor, ME, United States of America.
PLoS One. 2015 Oct 16;10(10):e0140729. doi: 10.1371/journal.pone.0140729. eCollection 2015.
Invariant Natural Killer T (iNKT) cells are a T cell subset expressing an invariant T Cell Receptor (TCR) that recognizes glycolipid antigens rather than peptides. The cells have both innate-like rapid cytokine release, and adaptive-like thymic positive selection. iNKT cell activation has been implicated in the pathogenesis of allergic asthma and inflammatory diseases, while reduced iNKT cell activation promotes infectious disease, cancer and certain autoimmune diseases such as Type 1 diabetes (T1D). Therapeutic means to reduce or deplete iNKT cells could treat inflammatory diseases, while approaches to promote their activation may have potential in certain infectious diseases, cancer or autoimmunity. Thus, we developed invariant TCR-specific monoclonal antibodies to better understand the role of iNKT cells in disease. We report here the first monoclonal antibodies specific for the mouse invariant TCR that by modifying the Fc construct can specifically deplete or activate iNKT cells in vivo in otherwise fully immuno-competent animals. We have used both the depleting and activating version of the antibody in the NOD model of T1D. As demonstrated previously using genetically iNKT cell deficient NOD mice, and in studies of glycolipid antigen activated iNKT cells in standard NOD mice, we found that antibody mediated depletion or activation of iNKT cells respectively accelerated and retarded T1D onset. In BALB/c mice, ovalbumin (OVA) mediated airway hyper-reactivity (AHR) was abrogated with iNKT cell depletion prior to OVA sensitization, confirming studies in knockout mice. Depletion of iNKT cells after sensitization had no effect on AHR in the conducting airways but did reduce AHR in the lung periphery. This result raises caution in the interpretation of studies that use animals that are genetically iNKT cell deficient from birth. These activating and depleting antibodies provide a novel tool to assess the therapeutic potential of iNKT cell manipulation.
不变自然杀伤T（iNKT）细胞是表达不变T细胞受体（TCR）的T细胞亚群，该受体识别糖脂抗原而非肽。这些细胞既具有类似先天免疫的快速细胞因子释放能力，又具有类似适应性免疫的胸腺阳性选择能力。iNKT细胞的激活与过敏性哮喘和炎症性疾病的发病机制有关，而iNKT细胞激活的减少则会促进传染病、癌症和某些自身免疫性疾病，如1型糖尿病（T1D）。减少或清除iNKT细胞的治疗手段可用于治疗炎症性疾病，而促进其激活的方法在某些传染病、癌症或自身免疫性疾病中可能具有潜力。因此，我们开发了针对不变TCR的单克隆抗体，以更好地了解iNKT细胞在疾病中的作用。我们在此报告了第一种针对小鼠不变TCR的单克隆抗体，通过修饰Fc结构，该抗体可以在完全具有免疫能力的动物体内特异性地清除或激活iNKT细胞。我们在T1D的非肥胖糖尿病（NOD）模型中使用了该抗体的清除和激活版本。正如先前使用基因敲除iNKT细胞的NOD小鼠所证明的，以及在标准NOD小鼠中对糖脂抗原激活的iNKT细胞的研究中所发现的，我们发现抗体介导的iNKT细胞清除或激活分别加速和延缓了T1D的发病。在BALB/c小鼠中，卵清蛋白（OVA）介导的松敏前iNKT细胞清除消除了气道高反应性（AHR），这证实了在基因敲除小鼠中的研究结果。致敏后iNKT细胞的清除对传导气道中的AHR没有影响，但确实降低了肺周边的AHR。这一结果提醒人们在解释使用出生时即基因敲除iNKT细胞的动物的研究时要谨慎。这些激活和清除抗体为评估iNKT细胞操纵的治疗潜力提供了一种新工具。
