Department of Pathology and Laboratory Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia V5Z 4H4, Canada.
J Immunol. 2011 May 1;186(9):5261-72. doi: 10.4049/jimmunol.1003615. Epub 2011 Mar 30.
B cell activation and Ab production in response to protein Ags requires presentation of peptides for recruitment of T cell help. We and others have recently demonstrated that B cells can also acquire innate help by presenting lipid Ags via CD1d to NKT cells. Given the newfound contribution of NKT cells to humoral immunity, we sought to identify the pathways that regulate CD1 molecule expression in human B cells. We show that ex vivo, activated and memory B cells expressed lower levels of CD1d compared with resting, naive, and marginal zone-like B cells. In vitro, CD1d was downregulated by all forms of B cell activation, leaving a narrow temporal window in which B cells could activate NKT cells. CD1c expression and function also decreased following activation by CD40L alone, whereas activation via the BCR significantly upregulated CD1c, particularly on marginal zone-like B cells. We found that the CD40L-induced downregulation of CD1d and CD1c correlated with diminished expression of retinoic acid receptor α (RARα) response genes, an effect that was reversed by RARα agonists. However, BCR-induced upregulation of CD1c was independent of the RAR pathway. Our findings that both CD1d and CD1c are upregulated by RARα signaling in human B cells is distinct from effects reported in dendritic cells, in which CD1c is inversely downregulated. One functional consequence of CD1d upregulation by retinoic acid was NKT cell cytotoxicity toward B cells. These results are central to our understanding of how CD1-restricted T cells may control humoral immunity.
B 细胞激活和针对蛋白质抗原的 Ab 产生需要呈递肽段以募集 T 细胞辅助。我们和其他人最近证明，B 细胞还可以通过 CD1d 呈递脂质抗原来获得先天辅助，从而激活 NKT 细胞。鉴于 NKT 细胞对体液免疫的新贡献，我们试图确定调节人 B 细胞中 CD1 分子表达的途径。我们发现，与静止、幼稚和边缘区样 B 细胞相比，体外激活和记忆 B 细胞表达的 CD1d 水平较低。体外，所有形式的 B 细胞激活均下调 CD1d，从而使 B 细胞激活 NKT 细胞的时间窗口变窄。仅通过 CD40L 激活时，CD1c 的表达和功能也会降低，而通过 BCR 激活则会显著上调 CD1c，尤其是边缘区样 B 细胞。我们发现，CD40L 诱导的 CD1d 和 CD1c 下调与维甲酸受体 α（RARα）反应基因的表达减少相关，RARα 激动剂可逆转这种作用。然而，BCR 诱导的 CD1c 上调与 RAR 途径无关。我们发现，RARα 信号在人 B 细胞中可同时上调 CD1d 和 CD1c，这与树突状细胞中的报道不同，在树突状细胞中，CD1c 呈负向下调。维甲酸对 CD1d 的上调会导致 NKT 细胞对 B 细胞的细胞毒性，这是一个功能后果。这些结果对于我们理解 CD1 限制的 T 细胞如何控制体液免疫至关重要。
