Motegi Sei-Ichiro, Okazawa Hideki, Murata Yoji, Kanazawa Yoshitake, Saito Yasuyuki, Kobayashi Hisae, Ohnishi Hiroshi, Oldenborg Per-Arne, Ishikawa Osamu, Matozaki Takashi
Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan.
Immunol Lett. 2008 Nov 16;121(1):52-60. doi: 10.1016/j.imlet.2008.08.005. Epub 2008 Sep 20.
SHPS-1 is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 and is abundant on the surface of CD11c(+) dendritic cells (DCs). We recently showed that SHPS-1 is essential for priming by DCs of CD4(+) T cells and for development of Th17 cell-mediated experimental autoimmunity. We have now further evaluated the importance of SHPS-1 and that of its ligand CD47 in contact hypersensitivity (CHS) to 2,4-dinitro-1-fluorobenzene (DNFB). Whereas the DNFB-induced CHS response was impaired in mice that express a mutant form of SHPS-1 lacking most of the cytoplasmic region, it was unaffected in CD47-deficient mice. Moreover, treatment of wild-type mice with mAbs to SHPS-1 that either block or do not block the binding of SHPS-1 to CD47 inhibited the CHS response. A mAb to CD47 had no such effect. The 2,4-dinitro-benzenesulfonic acid-induced proliferation of, and production of IFN-gamma or IL-17 by, T cells from DNFB-sensitized wild-type mice were inhibited by either mAb to SHPS-1 but not by that to CD47. In contrast, the blocking mAbs to SHPS-1, but not that to CD47, inhibited an allogeneic mixed leukocyte reaction. Both mAbs to SHPS-1, but not that to CD47, also inhibited the lipopolysaccharide- or polyinosinic-polycytidylic acid-induced production of TNF-alpha by DCs. These results suggest that SHPS-1 is essential for development of CHS, likely as a result of its positive regulation of the priming by DCs of CD4(+) T cells. However, such regulation by SHPS-1 does not appear to require its interaction with CD47.
SHPS-1是一种跨膜蛋白，可结合蛋白酪氨酸磷酸酶SHP-1和SHP-2，在CD11c(+)树突状细胞（DC）表面大量存在。我们最近发现，SHPS-1对于DC启动CD4(+) T细胞以及Th17细胞介导的实验性自身免疫的发展至关重要。我们现在进一步评估了SHPS-1及其配体CD47在对2,4-二硝基-1-氟苯（DNFB）的接触性超敏反应（CHS）中的重要性。虽然在表达缺乏大部分胞质区域的SHPS-1突变形式的小鼠中，DNFB诱导的CHS反应受损，但在CD47缺陷小鼠中未受影响。此外，用阻断或不阻断SHPS-1与CD47结合的抗SHPS-1单克隆抗体处理野生型小鼠会抑制CHS反应。抗CD47单克隆抗体没有这种作用。来自DNFB致敏野生型小鼠的T细胞的2,4-二硝基苯磺酸诱导的增殖以及IFN-γ或IL-17的产生，被抗SHPS-1单克隆抗体抑制，但不被抗CD47单克隆抗体抑制。相反，抗SHPS-1阻断单克隆抗体而非抗CD47单克隆抗体抑制了同种异体混合淋巴细胞反应。两种抗SHPS-1单克隆抗体而非抗CD47单克隆抗体也抑制了脂多糖或聚肌苷酸-聚胞苷酸诱导的DC产生TNF-α。这些结果表明，SHPS-1对于CHS的发展至关重要，这可能是由于其对DC启动CD4(+) T细胞的正向调节作用。然而，SHPS-1的这种调节作用似乎不需要其与CD47相互作用。
