TY - JOUR
T1 - De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR
AU - Kang, Johnthomas
AU - Huddleston, Stephen J.
AU - Fraser, Joanne M.
AU - Khoruts, Alexander
PY - 2008/5/1
Y1 - 2008/5/1
N2 - Although regulatory CD4+CD25+ forkhead box p3+ (Foxp3+) T cells (Tregs) are generally thought to arise in the thymus as a separate lineage of CD4 T cells, they can also be induced de novo in the periphery. Peripheral development of Tregs from naïve T cells is favored by low-intensity activation and absence of inflammation. We show here that absence of CD28 costimulation results in a modest decrease in activation of naïve, antigen-specific CD4 T cells under noninflammatory conditions and benefits their initial Foxp3 induction. However, expression of Foxp3 following T cell activation without CD28 costimulation remains sensitive to the antigen dose. Furthermore, basal CD28 costimulation is critical for survival of the induced Foxp3+ CD4 T cells, and their accumulation is abrogated in the absence of CD28. In contrast, pharmacologic blockade of mammalian target of rapamycin enhances lasting induction of Tregs, irrespective of the initial antigen dose used to activate the antigen-specific T cells. This finding may have important practical, clinical implication in development of tolerance protocols.
AB - Although regulatory CD4+CD25+ forkhead box p3+ (Foxp3+) T cells (Tregs) are generally thought to arise in the thymus as a separate lineage of CD4 T cells, they can also be induced de novo in the periphery. Peripheral development of Tregs from naïve T cells is favored by low-intensity activation and absence of inflammation. We show here that absence of CD28 costimulation results in a modest decrease in activation of naïve, antigen-specific CD4 T cells under noninflammatory conditions and benefits their initial Foxp3 induction. However, expression of Foxp3 following T cell activation without CD28 costimulation remains sensitive to the antigen dose. Furthermore, basal CD28 costimulation is critical for survival of the induced Foxp3+ CD4 T cells, and their accumulation is abrogated in the absence of CD28. In contrast, pharmacologic blockade of mammalian target of rapamycin enhances lasting induction of Tregs, irrespective of the initial antigen dose used to activate the antigen-specific T cells. This finding may have important practical, clinical implication in development of tolerance protocols.
KW - Cell differentiation
KW - Tolerance/suppression/anergy
UR - http://www.scopus.com/inward/record.url?scp=46949088630&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=46949088630&partnerID=8YFLogxK
U2 - 10.1189/jlb.1207851
DO - 10.1189/jlb.1207851
M3 - Article
C2 - 18270248
AN - SCOPUS:46949088630
SN - 0741-5400
VL - 83
SP - 1230
EP - 1239
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 5
ER -