Abstract
T cell receptor (TCR) ligation is required for the extrathymic differentiation of forkhead box p3(+) (Foxp3(+)) regulatory T cells. Several lines of evidence indicate that weak TCR stimulation favors induction of Foxp3 in the periphery; however, it remains to be determined how TCR ligand potency influences this process. We characterized the density and affinity of TCR ligand favorable for Foxp3 induction and found that a low dose of a strong agonist resulted in maximal induction of Foxp3 in vivo. Initial Foxp3 induction by weak agonist peptide could be enhanced by disruption of TCR-peptide major histocompatibility complex (pMHC) interactions or alteration of peptide dose. However, time course experiments revealed that Foxp3-positive cells induced by weak agonist stimulation are deleted, along with their Foxp3-negative counterparts, whereas Foxp3-positive cells induced by low doses of the strong agonist persist. Our results suggest that, together, pMHC ligand potency, density, and duration of TCR interactions define a cumulative quantity of TCR stimulation that determines initial peripheral Foxp3 induction. However, in the persistence of induced Foxp3(+) T cells, TCR ligand potency and density are noninterchangeable factors that influence the route to peripheral tolerance.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adoptive Transfer
-
Animals
-
Antibodies, Monoclonal / immunology
-
Antibodies, Monoclonal / pharmacology
-
Apoptosis / immunology
-
Cell Count
-
Cell Differentiation / immunology*
-
Cell Proliferation / drug effects
-
Coculture Techniques
-
Cytochromes c / immunology
-
DNA-Binding Proteins / genetics
-
Epitopes, T-Lymphocyte / immunology*
-
Epitopes, T-Lymphocyte / metabolism
-
Forkhead Transcription Factors / metabolism*
-
Histocompatibility Antigens Class II / immunology
-
Histocompatibility Antigens Class II / metabolism
-
Interleukin-2 / pharmacology
-
Ki-67 Antigen / metabolism
-
Ligands
-
Lymph Nodes / cytology
-
Lymphocyte Activation / immunology
-
Male
-
Mice
-
Mice, Inbred Strains
-
Mice, Knockout
-
Mice, Transgenic
-
Peptide Fragments / administration & dosage
-
Peptide Fragments / immunology
-
Peptide Fragments / metabolism
-
Phosphorylation
-
Protein Binding / drug effects
-
Protein Binding / immunology
-
Proto-Oncogene Proteins c-akt / metabolism
-
Receptors, Antigen, T-Cell / genetics
-
Receptors, Antigen, T-Cell / immunology*
-
Receptors, Antigen, T-Cell / metabolism
-
Spleen / cytology
-
T-Cell Antigen Receptor Specificity
-
T-Lymphocytes / drug effects
-
T-Lymphocytes / immunology*
-
T-Lymphocytes / metabolism*
-
T-Lymphocytes / transplantation
-
Transforming Growth Factor beta / pharmacology
Substances
-
Antibodies, Monoclonal
-
DNA-Binding Proteins
-
Epitopes, T-Lymphocyte
-
Forkhead Transcription Factors
-
Foxp3 protein, mouse
-
Histocompatibility Antigens Class II
-
Interleukin-2
-
Ki-67 Antigen
-
Ligands
-
Peptide Fragments
-
Rag2 protein, mouse
-
Receptors, Antigen, T-Cell
-
Transforming Growth Factor beta
-
Cytochromes c
-
Proto-Oncogene Proteins c-akt