title: TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo.
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.
authors.affiliation: Department of Immunology, Howard Hughes Medical Institute, New York, NY 10021, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gottschalk
authors.forename: Emily
authors.initials: E
authors.lastname: Corse
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D002452:Cell Count; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D045304:Cytochromes c / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000378:metabolism; D008024:Ligands; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D019394:Ki-67 Antigen; D008024:Ligands; D010446:Peptide Fragments; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt