Incomplete depletion and rapid regeneration of Foxp3+ regulatory T cells following anti-CD25 treatment in malaria-infected mice.
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 CD25(high)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.
Couper
Kevin N
KN
Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, U.K.
Blount
Daniel G
DG
de Souza
J Brian
JB
Suffia
Isabelle
I
Belkaid
Yasmine
Y
Riley
Eleanor M
EM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015704:CD4 Antigens / Q000032:analysis; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000032:analysis; D007074:Immunoglobulin G / Q000494:pharmacology; D007075:Immunoglobulin M / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008212:Lymphocyte Depletion / Q000379:methods*; D008288:Malaria / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010967:Plasmodium yoelii; D012038:Regeneration; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta