TNF-α antagonism generates a population of antigen-specific ECD4+CD25+ T cells that inhibit protective immunity in muriue histoplasmosis
TNF-α antagonism generates a population of antigen-specific ECD4+CD25+ T cells that inhibit protective immunity in muriue histoplasmosis
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DOI：
10.4049/jimmunol.180.2.1088
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发表时间：
2008-01-15
影响因子：
4.4
通讯作者：
Gibbons, Reta S.
中科院分区：
文献类型：
--
作者：
Deepe, George S., Jr.;Gibbons, Reta S.
在人类和小鼠中，使用肿瘤坏死因子-α拮抗剂治疗与包括播散性组织胞浆菌病在内的严重感染并发症有关。抑制内源性肿瘤坏死因子-α改变保护性免疫的机制尚不清楚。在这里，我们测试了中和这种细胞因子引发抑制免疫的T细胞出现的可能性。注射抗肿瘤坏死因子-α单抗的小鼠肺中的CD4(+)CD25(+)细胞比例和数量均高于对照组。这种升高在缺乏干扰素或GM-CSF的小鼠或那些给予高接种量的小鼠中没有观察到。表型分析显示，这些细胞缺乏自然调节性T细胞的许多特征，包括Foxp3。来自肿瘤坏死因子-α中和小鼠的CD4(+)CD25(+)细胞在体外抑制抗原特异性反应，但不是非特异性反应。体内CD25(+)细胞的清除恢复了给予抗肿瘤坏死因子-α单抗的小鼠的保护性免疫，过继转移CD4(+)CD25(+)细胞抑制了免疫。在体内外，IL-10的mAb均能逆转这种抑制作用。因此，中和肿瘤坏死因子-α与诱导群体调节性T细胞有关，该T细胞以抗原特异性的方式改变对组织胞浆的保护性免疫。
In both humans and mice, treatment with TNF-alpha antagonists is associated with serious infectious complications including disseminated histoplasmosis. The mechanisms by which inhibition of endogenous TNF-alpha alter protective immunity remain obscure. Herein, we tested the possibility that neutralization of this cytokine triggered the emergence of T cells that dampen immunity. The lungs of mice given mAb to TNF-alpha contained a higher proportion and number of CD4(+)CD25(+) cells than controls. This elevation was not observed in IFN-gamma- or GM-CSF-deficient mice or in those given a high inoculum. Phenotypic analysis revealed that these cells lacked many of the characteristics of natural regulatory T cells, including Foxp3. CD4(+)CD25(+) cells from TNF-alpha-neutralized mice suppressed Ag-specific, but not nonspecific, responses in vitro. Elimination of CD25(+) cells in vivo restored protective immunity in mice given mAb to TNF-alpha and adoptive transfer of CD4(+)CD25(+) cells inhibited immunity. In vitro and in vivo, the suppressive effect was reversed by mAb to IL-10. Thus, neutralization of TNF-alpha is associated with the induction of a population regulatory T cells that alter protective immunity in an Ag-specific manner to Histoplasma capsulatum.