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PMID: 17982074 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Raf signaling but not the ERK effector SAP-1 is required for regulatory T cell development.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 179 ·No. 10 ·2007-11-15 ·Pages 6836-44

Willoughby JE, Costello PS, Nicolas RH, Robinson NJ, Stamp G, Powrie F, Treisman R

Abstract

Regulatory T cells (T(reg)) play an important role in immune regulation. Their development in the thymus requires TCR activation and recognition of peptide-MHC, although the downstream signals controlling commitment to the lineage are unclear. To compare the requirements for positive selection and T(reg) development, we studied knockout and transgenic mice defective in Raf signaling and the ERK effector SRF accessory protein 1 (SAP-1), a member of the ternary complex factor family of Ets domain transcription factors. Although SAP-1 deficient mice display a severe defect in thymocyte positive selection, T(reg) development was unimpaired as assessed by expression of Foxp3 and the activation markers CD25, GITR, CTLA4, and CD103 in the CD4(+) cell population. In contrast, inhibition of Raf signaling by the interfering dominant negative Raf derivative reduced both Foxp3(+) and Foxp3(-) CD4(+) populations. In SAP-1-deficient CD4(+)CD25(+) T(reg) cells, TCR crosslinking efficiently induced ERK activation, but transcriptional induction of the immediate early gene Egr-1 was impaired. Nevertheless, neither deletion of SAP-1 nor expression of a dominant negative Raf derivative affected the ability of CD4(+)CD25(+) T(reg) cells to suppress CD4(+)CD25(-) cell proliferation in vitro. Finally the suppressive activity of CD4(+)CD25(+) T(reg) cells lacking SAP-1 in an in vivo colitis model was not significantly impaired. The signaling requirements for development of T(reg) cells in the thymus are thus distinct from those required for "conventional" T cell positive selection, and ERK signaling to SAP-1 is not required for the suppressive activity of T(reg) cells.

MeSH Terms
Animals Antigens, Differentiation Cell Proliferation Colitis/immunology,metabolism,pathology Disease Models, Animal Early Growth Response Protein 1/biosynthesis,genetics,immunology Extracellular Signal-Regulated MAP Kinases/genetics,immunology,metabolism Gene Expression Regulation/immunology Mice Mice, Transgenic Signal Transduction/genetics,immunology T-Lymphocytes, Regulatory/immunology,metabolism,pathology Thymus Gland/immunology,metabolism,pathology ets-Domain Protein Elk-4/genetics,immunology,metabolism raf Kinases/genetics,immunology,metabolism
Chemicals
Antigens, Differentiation Early Growth Response Protein 1 Egr1 protein, mouse Elk4 protein, mouse ets-Domain Protein Elk-4 raf Kinases Extracellular Signal-Regulated MAP Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Willoughby Jane E
Transcription Laboratory, Cancer Research United Kingdom London Research Institute, Lincoln's Inn Fields Laboratories, London, United Kingdom.
Costello Patrick S
Nicolas Robert H
Robinson Nicholas J
Stamp Gordon
Powrie Fiona
Treisman Richard
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Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
0022-1767
DOI
10.4049/jimmunol.179.10.6836
Published
2007-11-15
Pages
6836-44
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC2515877
Subset
IM
Grants
Wellcome Trust · United Kingdom
Wellcome Trust · 044651 · United Kingdom
External Links
PubMed source DOI: 10.4049/jimmunol.179.10.6836 PMC Full Text View journal details
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