Taylor A, Namba K
Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA.
Immunol Cell Biol. 2001 Aug;79(4):358-67. doi: 10.1046/j.1440-1711.2001.01022.x.
Recently, we have found that the neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) not only suppresses IFN-gamma production, but also induces TGF-beta1 production by activated effector T cells. These alpha-MSH- treated effector T cells function as regulatory T cells in that they suppress IFN-gamma production and hypersensitivity mediated by other effector T cells. Experimental autoimmune uveoretinitis (EAU) was suppressed in its severity and incidence in mice that were injected with primed T cells activated in vitro by APC and antigen in the presence of alpha-MSH. Moreover, it appeared that alpha-MSH had converted a population of effector T cells polarized to mediate hypersensitivity into a population of T cells that now mediated immunoregulation. To characterize these alpha-MSH- treated T cells, primed T cells were TCR-stimulated in the presence of alpha-MSH in vitro and their lymphokine profile was examined. Such effector T cells displayed enhanced levels of TGF-beta1 production and no IFN-gamma or IL-10, with IL-4 levels remaining unchanged in comparison with inactivated T cells. In addition, if soluble TGF-beta receptor II was added to cocultures of alpha-MSH-treated T cells and activated Th1 cells, the alpha-MSH-treated T cells could not suppress IFN-gamma production by the Th1 cells. These results suggest that alpha-MSH induces T cells with a regulatory lymphokine pattern, and that through their production of TGF-beta1 these cells suppress other effector T cells. Examination of the alpha-MSH-treated T cells showed that alpha-MSH did not alter the phosphorylation of CD3 molecules following TCR engagement. Primed T cells express the melanocortin 5 receptor (MC5r), a receptor that is linked to an intracellular signalling pathway shared by other cytokine receptors. Blocking the receptor with antibody prevented alpha-MSH from suppressing IFN-gamma production by the activated regulatory T cells, suggesting that alpha-MSH immunoregulation is through the MC5r on primed T cells. Surface staining and cell sorting of the alpha-MSH- treated primed T cells showed that the regulatory T cells are CD25+ CD4+ T cells. From these results we find that alpha-MSH can mediate the induction of CD25+ CD4+ regulatory T cells. These regulatory T cells require specific antigen for activation, but through non-specific TGF-beta1-mediated mechanisms they can suppress other effector T cells.
最近，我们发现神经肽α-黑素细胞刺激素（α-MSH）不仅能抑制γ干扰素的产生，还能诱导活化的效应T细胞产生转化生长因子β1（TGF-β1）。这些经α-MSH处理的效应T细胞发挥调节性T细胞的功能，因为它们能抑制其他效应T细胞介导的γ干扰素产生和超敏反应。在α-MSH存在的情况下，将经抗原呈递细胞（APC）和抗原体外活化的致敏T细胞注射到小鼠体内，实验性自身免疫性葡萄膜视网膜炎（EAU）的严重程度和发病率均受到抑制。此外，α-MSH似乎已将一群极化以介导超敏反应的效应T细胞转化为现在介导免疫调节的T细胞群体。为了表征这些经α-MSH处理的T细胞，将致敏T细胞在体外α-MSH存在的情况下进行T细胞受体（TCR）刺激，并检测其淋巴因子谱。与未活化的T细胞相比，这类效应T细胞显示出TGF-β1产生水平增强，且无γ干扰素或白细胞介素10（IL-10）产生，IL-4水平保持不变。此外，如果将可溶性TGF-β受体II添加到经α-MSH处理的T细胞与活化的Th1细胞的共培养物中，经α-MSH处理的T细胞就无法抑制Th1细胞产生γ干扰素。这些结果表明，α-MSH诱导具有调节性淋巴因子模式的T细胞，并且这些细胞通过产生TGF-β1来抑制其他效应T细胞。对经α-MSH处理的T细胞的检测表明，α-MSH在TCR结合后不会改变CD3分子的磷酸化。致敏T细胞表达黑皮质素5受体（MC5r），该受体与其他细胞因子受体共享的细胞内信号通路相连。用抗体阻断该受体可阻止α-MSH抑制活化调节性T细胞产生γ干扰素，这表明α-MSH免疫调节是通过致敏T细胞上的MC5r进行的。对经α-MSH处理的致敏T细胞进行表面染色和细胞分选表明，调节性T细胞是CD25+CD4+T细胞。从这些结果中我们发现，α-MSH可介导CD25+CD4+调节性T细胞的诱导。这些调节性T细胞需要特异性抗原进行活化，但通过非特异性TGF-β1介导的机制，它们可以抑制其他效应T细胞。
