Impaired SLAM-SLAM homotypic interaction between invariant NKT cells and dendritic cells affects differentiation of IL-4/IL-10-secreting NKT2 cells in nonobese diabetic mice
Impaired SLAM-SLAM homotypic interaction between invariant NKT cells and dendritic cells affects differentiation of IL-4/IL-10-secreting NKT2 cells in nonobese diabetic mice
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DOI：
10.4049/jimmunol.181.2.869
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发表时间：
2008-07-15
影响因子：
4.4
通讯作者：
Falcone, Marika
中科院分区：
文献类型：
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作者：
Baev, Denis V.;Caielli, Simone;Falcone, Marika
恒定 NKT (iNKT) 细胞诱导耐受和预防自身免疫的调节功能与特定的细胞因子谱相关，其中包括 IL-4 和 IL-10 等 2 型细胞因子的分泌（NKT2 细胞因子谱）。 iNKT 细胞分化为 2 型表型的机制尚不清楚。在此，我们表明，骨髓树突状细胞（mDC）上的表面受体信号淋巴细胞激活分子（SLAM）向iNKT细胞提供的共刺激信号对于NKT2定向至关重要。此外，我们还证明，自发发展为自身免疫性糖尿病的非肥胖糖尿病 (NOD) 小鼠中 NKT2 细胞因子表型的获取受损是由于 NOD mDC 产生的 SLAM 诱导信号缺陷所致。 C57BL/6 小鼠的成熟 mDC 表达 SLAM 并诱导 C57BL/6 或 NOD iNKT 细胞获得主要的 NKT2 细胞因子表型，以响应 iNKT 细胞特异性 Ag（α-半乳糖神经酰胺）的抗原刺激。相比之下，成熟的 NOD mDC 表达的 SLAM 水平明显较低，并且无法促进来自 NOD 或 C57BL/6 小鼠的 iNKT 细胞中 GATA-3（SLAM 诱导的细胞内信号）上调和 IL-4/IL-10 的产生。 NOD 小鼠携带 Slamf1 基因的遗传缺陷，该缺陷与双阳性胸腺细胞上 SLAM 表达的减少以及胸腺中 iNKT 细胞发育的改变有关。我们的数据表明，NOD 小鼠的遗传性 Slamf1 缺陷也会影响 mDC 等其他免疫细胞上的 SLAM 表达，从而严重损害 iNKT 细胞向调节性 NKT2 类型的外周分化。
The regulatory function of invariant NKT (iNKT) cells for tolerance induction and prevention of autoimmunity is linked to a specific cytokine profile that comprises the secretion of type 2 cytokines like IL-4 and IL-10 (NKT2 cytokine profile). The mechanism responsible for iNKT cell differentiation toward a type 2 phenotype is unknown. Herein we show that costimulatory signals provided by the surface receptor signaling lymphocytic activation molecule (SLAM) on myeloid dendritic cells (mDC) to iNKT cells is crucial for NKT2 orientation. Additionally, we demonstrate that the impaired acquisition of an NKT2 cytokine phenotype in nonobese diabetic (NOD) mice that spontaneously develop autoimmune diabetes is due to defective SLAM-induced signals generated by NOD mDC. Mature mDC of C57BL/6 mice express SLAM and induce C57BL/6 or NOD iNKT cells to acquire a predominant NKT2 cytokine phenotype in response to antigenic stimulation with the iNKT cell-specific Ag, the alpha-galactosylceramide. In contrast, mature NOD mDC express significantly lower levels of SLAM and are unable to promote GATA-3 (the SLAM-induced intracellular signal) up-regulation and IL-4/IL-10 production in iNKT cells from NOD or C57BL/6 mice. NOD mice carry a genetic defect of the Slamf1 gene that is associated with reduced SLAM expression on double-positive thymocytes and altered iNKT cell development in the thymus. Our data suggest that the genetic Slamf1 defect in NOD mice also affects SLAM expression on other immune cells such as the mDC, thus critically impairing the peripheral differentiation of iNKT cells toward a regulatory NKT2 type.