TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo Journal Article
| Authors: | Gottschalk, R. A.; Corse, E.; Allison, J. P. |
| Article 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. © 2010 Gottschalk et al. |
| Keywords: | protein kinase b; controlled study; protein phosphorylation; dna-binding proteins; nonhuman; lymph nodes; transcription factor foxp3; cell proliferation; forkhead transcription factors; ki-67 antigen; t-lymphocytes; animal cell; mouse; animals; mice; mice, knockout; apoptosis; spleen; transforming growth factor beta; animal experiment; protein binding; in vivo study; cell differentiation; phosphorylation; mice, transgenic; mice, inbred strains; t lymphocyte receptor; lymphocyte activation; antibodies, monoclonal; receptors, antigen, t-cell; peptide fragments; t-cell antigen receptor specificity; proto-oncogene proteins c-akt; protein induction; ligands; adoptive transfer; cell count; histocompatibility antigens class ii; major histocompatibility complex; epitopes, t-lymphocyte; concentration (parameters); interleukin-2; coculture techniques; cytochromes c |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 207 |
| Issue: | 8 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2010-01-01 |
| Start Page: | 1701 |
| End Page: | 1711 |
| Language: | English |
| DOI: | 10.1084/jem.20091999 |
| PUBMED: | 20660617 |
| PROVIDER: | scopus |
| PMCID: | PMC2916126 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 20 April 2011" - "CODEN: JEMEA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work