Ahn Justin S, Krishnadas Deepa K, Agrawal Babita
Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Int Immunol. 2007 Mar;19(3):227-37. doi: 10.1093/intimm/dxl139. Epub 2007 Feb 7.
The factors that influence the functionality of human CD4(+)CD25(+) regulatory T cells are not well understood. We sought to characterize the effects of dendritic cells (DCs) on the in vitro regulatory activity of CD4(+)CD25(+) T cells obtained from peripheral blood of healthy human donors. Flow cytometry showed that a higher proportion of CD4(+)CD25(+(High)) T cells expressed surface glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) and CTL-associated antigen 4 than CD4(+)CD25(-) or CD4(+)CD25(+(Med-low)) T cells. Intracellular Foxp3 was equivalently expressed on CD4(+)CD25(+(All)), CD4(+)CD25(+(High)), CD4(+)CD25(+(Med-low)) and CD4(+)CD25(-) T cell populations, irrespective of GITR and CTL-associated antigen 4 expression. CD4(+)CD25(+) T cells were isolated and then cultured in vitro with CD4(+)CD25(-) responder T cells and stimulated with anti-CD3 antibodies, and immature dendritic cells (iDCs), mature dendritic cells (mDCs), PBMCs or PBMCs plus anti-CD28 antibodies to provide co-stimulation. In addition, secretion of the T(h)1 cytokine IFN-gamma, IL-2 and the immunoregulatory cytokines, IL-10 and transforming growth factor (TGF)-beta, were also assessed in these cultures. We found that iDCs and mDCs were capable of reversing the suppression of proliferation mediated by CD4(+)CD25(+) regulatory T cells. However, the reversal of suppression by DCs was not dependent upon the increase of IFN-gamma and IL-2 production or inhibition of IL-10 and/or TGF-beta production. Therefore, DCs are able to reverse the suppressive effect of regulatory T cells independent of cytokine production. These results suggest for the first time that human DCs possess unique abilities which allow them to influence the functions of regulatory T cells in order to provide fine-tuning in the regulation of T cell responses.
影响人类CD4(+)CD25(+)调节性T细胞功能的因素尚未完全明确。我们试图阐明树突状细胞（DCs）对从健康人类供体外周血中获取的CD4(+)CD25(+) T细胞体外调节活性的影响。流式细胞术显示，与CD4(+)CD25(-)或CD4(+)CD25(+(中低)) T细胞相比，更高比例的CD4(+)CD25(+(高)) T细胞表达表面糖皮质激素诱导的肿瘤坏死因子受体家族相关蛋白（GITR）和CTL相关抗原4。细胞内Foxp3在CD4(+)CD25(+(全部))、CD4(+)CD25(+(高))、CD4(+)CD25(+(中低))和CD4(+)CD25(-) T细胞群体中表达相当，与GITR和CTL相关抗原4的表达无关。分离出CD4(+)CD25(+) T细胞，然后在体外与CD4(+)CD25(-)反应性T细胞一起培养，并用抗CD3抗体刺激，同时加入未成熟树突状细胞（iDCs）、成熟树突状细胞（mDCs）、外周血单核细胞（PBMCs）或PBMCs加抗CD28抗体以提供共刺激。此外，还在这些培养物中评估了Th1细胞因子IFN-γ、IL-2以及免疫调节细胞因子IL-10和转化生长因子（TGF）-β的分泌。我们发现iDCs和mDCs能够逆转CD4(+)CD25(+)调节性T细胞介导的增殖抑制。然而，DCs对抑制作用的逆转并不依赖于IFN-γ和IL-2产生的增加或IL-10和/或TGF-β产生的抑制。因此，DCs能够独立于细胞因子产生而逆转调节性T细胞的抑制作用。这些结果首次表明，人类DCs具有独特的能力，使其能够影响调节性T细胞的功能，从而在T细胞反应的调节中进行微调。
