PMID- 20805478
OWN - NLM
STAT- MEDLINE
DCOM- 20101028
LR  - 20240322
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 107
IP  - 37
DP  - 2010 Sep 14
TI  - Enhancement of antigen-specific Treg vaccination in vivo.
PG  - 16246-51
LID - 10.1073/pnas.1007422107 [doi]
AB  - 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 P2x7 receptor controlling Ca2(+) influx. The resulting Tregs exhibit 
      increased stability of Foxp3 expression even when generated in TGFbeta-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.
FAU - Daniel, Carolin
AU  - Daniel C
AD  - Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, 
      MA 02115, USA.
FAU - Wennhold, Kerstin
AU  - Wennhold K
FAU - Kim, Hye-Jung
AU  - Kim HJ
FAU - von Boehmer, Harald
AU  - von Boehmer H
LA  - eng
GR  - R37 AI053102/AI/NIAID NIH HHS/United States
GR  - NIH-AI-53102/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100830
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antigens)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxp3 protein, mouse)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Interleukin-2)
RN  - 0 (Interleukin-2 Receptor alpha Subunit)
RN  - 0 (P2rx7 protein, mouse)
RN  - 0 (Receptors, Purinergic P2)
RN  - 0 (Receptors, Purinergic P2X7)
RN  - 130068-27-8 (Interleukin-10)
RN  - 9HW64Q8G6G (Everolimus)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antigens/*immunology
MH  - Cell Proliferation/drug effects
MH  - Everolimus
MH  - Female
MH  - Forkhead Transcription Factors/immunology
MH  - Immunosuppressive Agents/pharmacology
MH  - Interleukin-10/immunology
MH  - Interleukin-2/immunology
MH  - Interleukin-2 Receptor alpha Subunit/immunology
MH  - Lymphocyte Activation
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Receptors, Purinergic P2/immunology
MH  - Receptors, Purinergic P2X7
MH  - Sirolimus/analogs & derivatives/pharmacology
MH  - T-Lymphocytes, Regulatory/cytology/drug effects/*immunology
MH  - Vaccination
PMC - PMC2941325
COIS- The authors declare no conflict of interest.
EDAT- 2010/09/02 06:00
MHDA- 2010/10/29 06:00
PMCR- 2011/03/14
CRDT- 2010/09/01 06:00
PHST- 2010/09/01 06:00 [entrez]
PHST- 2010/09/02 06:00 [pubmed]
PHST- 2010/10/29 06:00 [medline]
PHST- 2011/03/14 00:00 [pmc-release]
AID - 1007422107 [pii]
AID - 201007422 [pii]
AID - 10.1073/pnas.1007422107 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16246-51. doi: 
      10.1073/pnas.1007422107. Epub 2010 Aug 30.