Enhancement of antigen-specific Treg vaccination in vivo.
The conversion of naive T cells into Treg can be achieved in vivo by delivery of antigen under subimmunogenic conditions. Here we have examined several drugs for their ability to enhance the conversion process in vivo and have found that the rapamycin analog everolimus potently enhances Treg conversion by interfering with T-cell costimulation, reducing cell division and thereby activation of DNA methyltransferase 1 as well as by reducing T-cell activation through the ATP-gated P2×7 receptor controlling Ca2(+) influx. The resulting Tregs exhibit increased stability of Foxp3 expression even when generated in TGFβ-containing media in vitro. Thus the mammalian target of rapamycin (mTOR) inhibitor everolimus in addition to inhibiting immune responses enhances Treg conversion by several distinct pathways. The converted Tregs can be further expanded by injection of IL-2/IL-2ab complexes. These complexes also increase the number of CD25(+)Foxp3(-) cells that, however, do not represent cytokine secreting effector cells but anergic cells, some of which can secrete IL-10 and can themselves be considered regulatory T cells as well. The combined use of everolimus and IL-2/IL-2ab complexes in vivo makes it feasible to achieve highly effective antigen-driven conversion of naive T cells into Treg and their expansion in vivo and thereby the described protocols constitute important tools to achieve immunological tolerance by Treg vaccination.
Daniel
Carolin
C
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Wennhold
Kerstin
K
Kim
Hye-Jung
HJ
von Boehmer
Harald
H
D000818:Animals; D000941:Antigens / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D000068338:Everolimus; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018048:Receptors, Purinergic P2 / Q000276:immunology; D058486:Receptors, Purinergic P2X7; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D014611:Vaccination
D000941:Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D016753:Interleukin-10; D000068338:Everolimus; D020123:Sirolimus
Annu Rev Physiol. 2009;71:333-59
18851707
J Immunol. 2009 Jun 1;182(11):6648-52
19454658
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12055-60
19567830
Blood. 2005 Jun 15;105(12):4743-8
15746082
J Exp Med. 1994 Jul 1;180(1):25-34
8006585
J Exp Med. 2010 Aug 2;207(8):1701-11
20660617
Science. 2006 Mar 31;311(5769):1924-7
16484453
J Exp Med. 2009 Apr 13;206(4):751-60
19332874
J Exp Med. 2003 Dec 15;198(12):1875-86
14676299
Immunity. 2005 Mar;22(3):329-41
15780990
Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3479-84
18299571
Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7797-802
18509048
Nat Immunol. 2005 Dec;6(12):1219-27
16244650
Int Immunol. 2005 Apr;17(4):335-42
15710910
J Exp Med. 2007 Jul 9;204(7):1543-51
17591856
J Exp Med. 2004 May 17;199(10):1401-8
15148338
J Exp Med. 2005 Aug 1;202(3):445-55
16061730
Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8886-91
12857946
Immunity. 2009 May;30(5):626-35
19464985
Immunity. 2008 Jul 18;29(1):114-26
18617425
Nat Immunol. 2002 Aug;3(8):756-63
12089509
Eur J Immunol. 2008 Jun;38(6):1654-63
18493985
Methods Mol Biol. 2011;707:173-85
21287335
PLoS One. 2008 Feb 20;3(2):e1612
18286169
Nat Immunol. 2000 Jul;1(1):54-8
10881175
Immunity. 2009 Jun 19;30(6):832-44
19538929
Physiol Rev. 2002 Oct;82(4):1013-67
12270951
J Biol Chem. 1993 Apr 15;268(11):8199-203
8463330
J Exp Med. 1963 Apr 1;117:621-31
14027809
J Exp Med. 2008 Mar 17;205(3):565-74
18283119
Eur J Immunol. 2007 Sep;37(9):2378-89
17694575
Nat Protoc. 2006;1(2):653-61
17802642
Nat Immunol. 2009 Oct;10(10):1057-63
19701188