Induction of regulatory T cell-resistant helper CD4+ T cells by bacterial vector
Induction of regulatory T cell-resistant helper CD4+ T cells by bacterial vector
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DOI：
10.1182/blood-2007-09-113761
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发表时间：
2008-02-01
期刊：
影响因子：
20.3
通讯作者：
Gnjatic, Sacha
中科院分区：
文献类型：
--
作者：
Nishikawa, Hiroyoshi;Tsuji, Takernasa;Gnjatic, Sacha
鼠伤寒沙门菌通过III型分泌传递癌症/睾丸抗原NY-ESO-1 （S typhimurium-NY-ESO-1）在小鼠中被证明是一种有效的癌症疫苗构建物，并在体外刺激NY-ESO-1自发免疫的癌症患者体内特异性CD8(+)/CD4(+) T细胞。我们还发现，对NY-ESO-1没有自发免疫的个体具有特异性的CD4(+) T细胞前体，在CD4(+)CD25（+）调节性T （Treg）细胞的严格控制下，对NY-ESO-1具有高亲和力。我们现在发现，在健康供体和没有NY-ESO-1自发免疫的黑色素瘤患者中，S鼠伤寒-NY-ESO-1在体外诱导CD4(+) T辅助1 （Th1）细胞识别来自这些高亲和力NY-ESO-1特异性初始前体的自然加工抗原。与肽刺激相比，S鼠伤寒- ny - eso -1诱导特异性Th1细胞不需要体外消耗CD4(+)CD25(+) Treg细胞，并且这种普遍作用部分被干扰素-6或糖皮质激素诱导的TNF受体（GITR）信号的破坏所阻断。此外，鼠伤寒沙门氏菌。-诱导的Th1细胞比肽诱导的Th1细胞具有更高的GITR表达，并且以GITR依赖的方式抵抗CD4(+)CD25(+) Treg细胞的抑制。我们提出S鼠伤寒- ny - eso -1诱导抗原特异性t细胞反应，抵抗CD4(+)CD25(+) Treg细胞的抑制。
Salmonella typhimurium engineered to deliver cancer/testis antigen NY-ESO-1 through type III secretion (S typhimurium-NY-ESO-1) was shown to be an efficient cancer vaccine construct in mice and to stimulate NY-ESO-1-specific CD8(+)/CD4(+) T cells in vitro in patients with cancer with NY-ESO-1 spontaneous immunity. We also showed that individuals without spontaneous immunity to NY-ESO-1 had specific CD4(+) T-cell precursors with high avidity to NY-ESO-1 under tight control by CD4(+)CD25(+) regulatory T (Treg) cells. We now found that in healthy donors and patients with melanoma without NY-ESO-1 spontaneous immunity, S typhimurium-NY-ESO-1 elicits CD4(+) T helper 1 (Th1) cells in vitro recognizing naturally processed antigen from these high-avidity NY-ESO-1-specific naive precursors. In contrast to peptide stimulation, induction of specific Th1 cells with S typhimurium-NY-ESO-1 did not require in vitro depletion of CD4(+)CD25(+) Treg cells, and this prevailing effect was partially blocked by disruption of interieukin-6 or glucocorticoid-induced TNF receptor (GITR) signals. Furthermore, S typhimurium.-induced Th1 cells had higher GITR expression than peptide-induced Th1 cells and were resistant to suppression by CD4(+)CD25(+) Treg cells in a GITR-dependent fashion. We propose that S typhimurium-NY-ESO-1 induces antigen-specific T-cell responses that are resistant to suppression by CD4(+)CD25(+) Treg cells.