Incomplete depletion and rapid regeneration of Foxp3+ regulatory T cells following anti-CD25 treatment in malaria-infected mice

被引:125
作者
Couper, Kevin N.
Blount, Daniel G.
de Souza, J. Brian
Suffia, Isabelle
Belkaid, Yasmine
Riley, Eleanor M.
机构
[1] Univ London London Sch Hyg & Trop Med, Dept Infect & Trop Dis, Immunol Unit, London WC1E 7HT, England
[2] UCL, Sch Med, Dept Immunol & Mol Pathol, London W1N 8AA, England
[3] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.4049/jimmunol.178.7.4136
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Investigation of the role of regulatory T cells (Treg) in model systems is facilitated by their depletion using anti-CD25 Abs, but there has been considerable debate about the effectiveness of this strategy. In this study, we have compared the depletion and repopulation of CD4(+)CD25(+)Foxp3(+) Treg in uninfected and malaria-infected mice using 7D4 and/or PC61 anti-CD25 Abs. We find that numbers and percentages of CD25(high) cells, but not Foxp3(+) cells, are transiently reduced after 7D4 treatment, whereas treatment with PC61 alone or in combination with 7D4 (7D4 plus PC61) reduces but does not eliminate Foxp3+ cells for up to 2 wk. Importantly, all protocols fail to eliminate significant populations of CD25(-)Foxp3(+) or CD25(low)Foxp3(+) cells, which retain potent regulatory capacity. By adoptive transfer we show that repopulation of the spleen by CD25high Foxp3(+) cells results from the re-expression of CD25 on peripheral populations of CD25(-)Foxp3(+) but not from the conversion of peripheral Foxp3(-) cells. CD25(high)Foxp3(+) repopulation occurs more rapidly in 7D4-treated mice than in 7D4 plus PC61-treated mice, reflecting ongoing clearance of emergent CD25(+)Foxp3(+) cells by persistent PC61 Ab. However, in 7D4 plus PC61-treated mice undergoing acute malaria infection, repopulation of the spleen by CD25(+)Foxp3(+) cells occurs extremely rapidly, with malaria infection driving proliferation and CD25 expression in peripheral CD4(+)CD25(-)Foxp3(-) cells and/or conversion of CD4(+)CD25(-)Foxp3(-) cells. Finally, we reveal an essential role for IL-2 for the re-expression of CD25 by Foxp3(+) cells after anti-CD25 treatment and observe that TGF-beta is required, in the absence of CD25 and IL-2, to maintain splenic Foxp3(+) cell numbers and a normal ratio of Treg:non-Treg cells.
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收藏
页码:4136 / 4146
页数:11
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