Selective Survival of Naturally Occurring Human CD4+CD25+Foxp3+ Regulatory T Cells Cultured with Rapamycin

Naturally occurring CD4(+)CD25(+) regulatory T (nTreg) cells are essential for maintaining T cell tolerance to self Ags. We show that discrimination of human Treg from effector CD4(+)CD25(+) non-nTreg cells and their selective survival and proliferation can now be achieved using rapamycin (sirolimus...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2007-01, Vol.178 (1), p.320-329
Main Authors: Strauss, Laura, Whiteside, Theresa L, Knights, Ashley, Bergmann, Christoph, Knuth, Alexander, Zippelius, Alfred
Format: Article
Language:English
Subjects:
Annexin A5 - metabolism
Antigens, CD - analysis
Antigens, CD - metabolism
Antigens, Differentiation - analysis
Antigens, Differentiation - metabolism
Autoantigens - immunology
CD4 Antigens - analysis
Cell Culture Techniques
Cell Survival - drug effects
Cells, Cultured
CTLA-4 Antigen
Forkhead Transcription Factors - analysis
Forkhead Transcription Factors - metabolism
Glucocorticoid-Induced TNFR-Related Protein - analysis
Glucocorticoid-Induced TNFR-Related Protein - metabolism
Humans
Interleukin-2 - pharmacology
Interleukin-2 Receptor alpha Subunit - analysis
Interleukin-2 Receptor alpha Subunit - metabolism
L-Selectin - analysis
L-Selectin - metabolism
Phenotype
Receptors, Antigen, T-Cell - drug effects
Receptors, CCR7
Receptors, Chemokine - analysis
Receptors, Chemokine - metabolism
Self Tolerance
Sirolimus - pharmacology
T-Lymphocytes, Regulatory - drug effects
T-Lymphocytes, Regulatory - immunology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Naturally occurring CD4(+)CD25(+) regulatory T (nTreg) cells are essential for maintaining T cell tolerance to self Ags. We show that discrimination of human Treg from effector CD4(+)CD25(+) non-nTreg cells and their selective survival and proliferation can now be achieved using rapamycin (sirolimus). Human purified CD4(+)CD25(high) T cell subsets stimulated via TCR and CD28 or by IL-2 survived and expanded up to 40-fold in the presence of 1 nM rapamycin, while CD4(+)CD25(low) or CD4(+)CD25(-) T cells did not. The expanding pure populations of CD4(+)CD25(high) T cells were resistant to rapamycin-accelerated apoptosis. In contrast, proliferation of CD4(+)CD25(-) T cells was blocked by rapamycin, which induced their apoptosis. The rapamycin-expanded CD4(+)CD25(high) T cell populations retained a broad TCR repertoire and, like CD4(+) CD25(+) T cells freshly obtained from the peripheral circulation, constitutively expressed CD25, Foxp3, CD62L, glucocorticoid-induced TNFR family related protein, CTLA-4, and CCR-7. The rapamycin-expanded T cells suppressed proliferation and effector functions of allogeneic or autologous CD4(+) and CD8(+) T cells in vitro. They equally suppressed Ag-specific and nonspecific responses. Our studies have defined ex vivo conditions for robust expansion of pure populations of human nTreg cells with potent suppressive activity. It is expected that the availability of this otherwise rare T cell subset for further studies will help define the molecular basis of Treg-mediated suppression in humans.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.178.1.320