PMID- 19801514
OWN - NLM
STAT- MEDLINE
DCOM- 20091110
LR  - 20211203
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 183
IP  - 8
DP  - 2009 Oct 15
TI  - Dominant role of antigen dose in CD4+Foxp3+ regulatory T cell induction and 
      expansion.
PG  - 4895-903
LID - 10.4049/jimmunol.0901459 [doi]
AB  - The definitions of tolerogenic vs immunogenic dendritic cells (DC) remain 
      controversial. Immature DC have been shown to induce T regulatory cells (Treg) 
      specific for foreign and allogeneic Ags. However, we have previously reported 
      that mature DC (mDC) prevented the onset of autoimmune diabetes, whereas immature 
      DC (iDC) were therapeutically ineffective. In this study, islet-specific CD4(+) T 
      cells from BDC2.5 TCR-transgenic mice were stimulated in the absence of exogenous 
      cytokine with iDC or mDC pulsed with high- or low-affinity antigenic peptides and 
      examined for Treg induction. Both iDC and mDC presenting low peptide doses 
      induced weak TCR signaling via the Akt/mammalian target of rapamycin (mTOR) 
      pathway, resulting in significant expansion of Foxp3(+) Treg. Furthermore, 
      unpulsed mDC, but not iDC, also induced Treg. High peptide doses induced strong 
      Akt/mTOR signaling and favored the expansion of Foxp3(neg) Th cells. The inverse 
      correlation of Foxp3 and Akt/mTOR signaling was also observed in DO11.10 and 
      OT-II TCR-transgenic T cells and was recapitulated with anti-CD3/CD28 stimulation 
      in the absence of DC. IL-6 production in these cultures correlated positively 
      with Ag dose and inversely with Treg expansion. Studies with T cells or DC from 
      IL-6(-/-) mice revealed that IL-6 production by T cells was more important in the 
      inhibition of Treg induction at low Ag doses. These studies indicate that the 
      strength of Akt/mTOR signaling, a critical T cell-intrinsic determinant for Treg 
      vs Th induction, can be controlled by adjusting the dose of antigenic peptide. 
      Furthermore, this operates in a dominant fashion over DC phenotype and cytokine 
      production.
FAU - Turner, Michael S
AU  - Turner MS
AD  - Department of Immunology, University of Pittsburgh School of Medicine, 
      Pittsburgh, PA 15261, USA.
FAU - Kane, Lawrence P
AU  - Kane LP
FAU - Morel, Penelope A
AU  - Morel PA
LA  - eng
GR  - R01 GM080398-02/GM/NIGMS NIH HHS/United States
GR  - T32 CA082084-10/CA/NCI NIH HHS/United States
GR  - 5T32CA82084-10/CA/NCI NIH HHS/United States
GR  - R01 GM080398-03/GM/NIGMS NIH HHS/United States
GR  - R01 GM080398/GM/NIGMS NIH HHS/United States
GR  - T32 CA082084/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Antibodies)
RN  - 0 (Antigens)
RN  - 0 (CD28 Antigens)
RN  - 0 (CD3 Complex)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cytokines)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxp3 protein, mouse)
RN  - 0 (Interleukin-6)
RN  - 0 (Peptides)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 9006-59-1 (Ovalbumin)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antibodies/immunology
MH  - Antigens/*immunology
MH  - CD28 Antigens/drug effects/immunology/metabolism
MH  - CD3 Complex/drug effects/immunology/metabolism
MH  - CD4-Positive T-Lymphocytes/*immunology/metabolism
MH  - Carrier Proteins/immunology/metabolism
MH  - Coculture Techniques
MH  - Cytokines/biosynthesis/immunology
MH  - Dendritic Cells/*immunology/metabolism
MH  - Diabetes Mellitus, Type 1/*immunology
MH  - Dose-Response Relationship, Immunologic
MH  - Forkhead Transcription Factors/immunology
MH  - Interleukin-6/genetics/immunology/*metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred NOD
MH  - Mice, Knockout
MH  - Oncogene Protein v-akt/immunology/metabolism
MH  - Ovalbumin/immunology
MH  - Peptides/immunology
MH  - Phosphotransferases (Alcohol Group Acceptor)/immunology/metabolism
MH  - Receptors, Antigen, T-Cell/immunology/metabolism
MH  - Signal Transduction/immunology
MH  - T-Lymphocytes, Regulatory/*immunology/metabolism
MH  - TOR Serine-Threonine Kinases
PMC - PMC3142864
MID - NIHMS138209
EDAT- 2009/10/06 06:00
MHDA- 2009/11/11 06:00
PMCR- 2011/07/25
CRDT- 2009/10/06 06:00
PHST- 2009/10/06 06:00 [entrez]
PHST- 2009/10/06 06:00 [pubmed]
PHST- 2009/11/11 06:00 [medline]
PHST- 2011/07/25 00:00 [pmc-release]
AID - 183/8/4895 [pii]
AID - 10.4049/jimmunol.0901459 [doi]
PST - ppublish
SO  - J Immunol. 2009 Oct 15;183(8):4895-903. doi: 10.4049/jimmunol.0901459.