Chen Xiuxu, Wang Xiaohua, Keaton Jason M, Reddington Faye, Illarionov Petr A, Besra Gurdyal S, Gumperz Jenny E
Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
J Immunol. 2007 May 15;178(10):6181-90. doi: 10.4049/jimmunol.178.10.6181.
CD1d molecules present both self Ags and microbial lipids to NKT cells. Previous studies have established that CD1d lysosomal trafficking is required for presentation of autoantigens to murine invariant NKT cells. We show in this study that this is not necessary for autoantigen presentation by human CD1d, but significantly affects the presentation of exogenous Ags. Wild-type and tail-deleted CD1d molecules stimulated similar autoreactive responses by human NKT clones, whereas presentation of exogenous lipids by tail-deleted CD1d was highly inefficient. Chloroquine treatment markedly inhibited exogenous Ag presentation by wild-type CD1d transfectants, but did not affect NKT autoreactive responses. Conversely, APC expression of HLA-DRalphabeta and the invariant chain (Ii) was associated with faster internalization of CD1d into the endocytic system and enhanced CD1d-mediated presentation of exogenous Ags, but did not appear to augment NKT autoreactivity. Knockdown of the Ii by small interfering RNA resulted in reduced CD1d surface expression and slower internalization in HLA-DR+ APCs, but not HLA-DR- APCs, demonstrating a direct effect of MHC/Ii complexes on CD1d trafficking. CD1d-mediated presentation of exogenous Ags was much more efficient in immature dendritic cells, which actively recycle MHC class II molecules through the endocytic system, than in mature dendritic cells that have stabilized MHC class II expression at the cell surface, suggesting a physiological role for MHC/Ii complexes in modulating CD1d function. These results indicate that autoantigens and exogenous lipids are acquired by human CD1d at distinct cellular locations, and that Ii trafficking selectively regulates CD1d-mediated presentation of extracellular Ags.
CD1d分子将自身抗原和微生物脂质呈递给自然杀伤T细胞（NKT细胞）。先前的研究已证实，CD1d的溶酶体运输对于向小鼠恒定自然杀伤T细胞呈递自身抗原是必需的。我们在本研究中表明，这对于人CD1d呈递自身抗原并非必要，但会显著影响外源性抗原的呈递。野生型和尾部缺失的CD1d分子刺激人NKT克隆产生相似的自身反应性应答，而尾部缺失的CD1d对外源性脂质的呈递效率极低。氯喹处理显著抑制野生型CD1d转染细胞对外源性抗原的呈递，但不影响NKT细胞的自身反应性应答。相反，HLA-DRαβ和恒定链（Ii）在抗原呈递细胞（APC）中的表达与CD1d更快地内化到内吞系统以及增强CD1d介导的外源性抗原呈递相关，但似乎并未增强NKT细胞的自身反应性。通过小干扰RNA敲低Ii导致HLA-DR+抗原呈递细胞中CD1d表面表达降低和内化减慢，但在HLA-DR-抗原呈递细胞中则不然，这表明MHC/Ii复合物对CD1d运输有直接影响。与已在细胞表面稳定表达MHC II类分子的成熟树突状细胞相比，在通过内吞系统积极循环MHC II类分子的未成熟树突状细胞中，CD1d介导的外源性抗原呈递效率要高得多，这表明MHC/Ii复合物在调节CD1d功能方面具有生理作用。这些结果表明，人CD1d在不同的细胞位置获取自身抗原和外源性脂质，并且Ii运输选择性地调节CD1d介导的细胞外抗原呈递。
