Sieling P A, Porcelli S A, Duong B T, Spada F, Bloom B R, Diamond B, Hahn B H
Division of Dermatology and Rheumatology, University of California School of Medicine, Los Angeles, CA 90095, USA.
J Immunol. 2000 Nov 1;165(9):5338-44. doi: 10.4049/jimmunol.165.9.5338.
To understand the mechanism of T cell help for IgG production in systemic lupus erythematosus (SLE) we investigated the response of CD4- and CD8-negative (double-negative (DN)) T cells because 1) DN T cells are present at unusually high frequency in patients with SLE and can induce pathogenic autoantibodies; 2) the DN T cell repertoire includes cells restricted by CD1 Ag-presenting molecules; and 3) CD1c is expressed on a population of circulating B cells. We derived DN T cell lines from SLE patients and healthy individuals. In the presence of CD1(+) APCs, DN T cell lines from SLE patients produced both IL-4 and IFN-gamma, whereas DN T cells from healthy donors produced IFN-gamma, but no IL-4. In general, cells from patients with highly active disease produced high levels of IFN-gamma; cells from those with little activity produced high IL-4. Coculture of CD1c-directly reactive T cells from healthy donors with CD1c(+) B cells elicited IgM Abs, but little or no IgG. In contrast, CD1c-directly reactive T cells from SLE patients induced isotype switching, with a striking increase in IgG production. Neutralizing Abs to CD1c inhibited the ability of DN T cells to induce IgG production from CD1c(+) B cells, further indicating that CD1c mediated the T and B cell interaction. IgG production was also inhibited by neutralizing Abs to IL-4, correlating with the cytokine pattern of DN T cells derived from these patients. The data suggest that CD1c-restricted T cells from SLE patients can provide help to CD1c(+) B cells for IgG production and could therefore promote pathogenic autoantibody responses in SLE.
为了解系统性红斑狼疮（SLE）中T细胞辅助IgG产生的机制，我们研究了CD4和CD8阴性（双阴性（DN））T细胞的反应，原因如下：1）DN T细胞在SLE患者中以异常高的频率存在，并且可以诱导致病性自身抗体；2）DN T细胞库包括受CD1抗原呈递分子限制的细胞；3）CD1c在一群循环B细胞上表达。我们从SLE患者和健康个体中获得了DN T细胞系。在存在CD1(+)抗原呈递细胞（APC）的情况下，SLE患者的DN T细胞系产生IL-4和IFN-γ，而健康供体的DN T细胞产生IFN-γ，但不产生IL-4。一般来说，疾病高度活跃患者的细胞产生高水平的IFN-γ；活动较少患者的细胞产生高水平的IL-4。健康供体中与CD1c直接反应的T细胞与CD1c(+) B细胞共培养可诱导产生IgM抗体，但很少或不产生IgG。相比之下，SLE患者中与CD1c直接反应的T细胞诱导了同种型转换，IgG产生显著增加。针对CD1c的中和抗体抑制了DN T细胞诱导CD1c(+) B细胞产生IgG的能力，进一步表明CD1c介导了T细胞和B细胞的相互作用。针对IL-4的中和抗体也抑制了IgG的产生，这与这些患者来源的DN T细胞的细胞因子模式相关。数据表明，SLE患者中受CD1c限制的T细胞可以为CD1c(+) B细胞产生IgG提供辅助，因此可能促进SLE中的致病性自身抗体反应。
