Hegde Subramanya, Jankowska-Gan Ewa, Roenneburg Drew A, Torrealba Jose, Burlingham William J, Gumperz Jenny E
Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
J Leukoc Biol. 2009 Oct;86(4):757-68. doi: 10.1189/jlb.0209059.
NKT cells have been shown to promote peripheral tolerance in a number of model systems, yet the processes by which they exert their regulatory effects remain poorly understood. Here, we show that soluble factors secreted by human NKT cells instruct human peripheral blood monocytes to differentiate into myeloid APCs that have suppressive properties. NKT instructed monocytes acquired a cell surface phenotype resembling myeloid DCs. However, whereas control DCs that were generated by culturing monocytes with recombinant GM-CSF and IL-4 had a proinflammatory phenotype characterized by the production of IL-12 with little IL-10, NKT-instructed APCs showed the opposite cytokine production profile of high IL-10 with little or no IL-12. The control DCs efficiently stimulated peripheral blood T cell IFN-gamma secretion and proliferation, whereas NKT-instructed APCs silenced these T cell responses. Exposure to NKT cell factors had a dominant effect on the functional properties of the DCs, since DCs differentiated by recombinant GM-CSF and IL-4 in the presence of NKT cell factors inhibited T cell responses. To confirm their noninflammatory effects, NKT-instructed APCs were tested in an in vivo assay that depends on the activation of antigen-specific human T cells. Control DCs promoted substantial tissue inflammation; however, despite a marked neutrophilic infiltrate, there was little edema in the presence of NKT-instructed APCs, suggesting the inflammatory cascade was held in check. These results point to a novel pathway initiated by NKT cells that can contribute to the regulation of human antigen-specific Th1 responses.
在许多模型系统中，自然杀伤T细胞（NKT细胞）已被证明可促进外周耐受，但它们发挥调节作用的具体过程仍知之甚少。在此，我们发现人类NKT细胞分泌的可溶性因子可指导人类外周血单核细胞分化为具有抑制特性的髓样抗原呈递细胞（APC）。NKT细胞指导下的单核细胞获得了类似于髓样树突状细胞的细胞表面表型。然而，用重组粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白细胞介素-4（IL-4）培养单核细胞产生的对照树突状细胞具有促炎表型，其特征是产生白细胞介素-12且几乎不产生白细胞介素-10，而NKT细胞指导下的APC则呈现相反的细胞因子分泌谱，即高分泌白细胞介素-10且几乎不分泌或不分泌白细胞介素-12。对照树突状细胞能有效刺激外周血T细胞分泌γ干扰素并增殖，而NKT细胞指导下的APC则抑制这些T细胞反应。由于在NKT细胞因子存在的情况下，由重组GM-CSF和IL-4分化产生的树突状细胞抑制了T细胞反应，因此暴露于NKT细胞因子对树突状细胞的功能特性具有主导作用。为了证实它们的非炎性作用，在一项依赖抗原特异性人类T细胞激活的体内试验中对NKT细胞指导下的APC进行了检测。对照树突状细胞引发了大量组织炎症；然而，尽管存在明显的嗜中性粒细胞浸润，但在NKT细胞指导下的APC存在时几乎没有水肿，这表明炎症级联反应受到了抑制。这些结果表明，NKT细胞启动了一条新的途径，可有助于调节人类抗原特异性Th1反应。
