Raf signaling but not the ERK effector SAP-1 is required for regulatory T cell development.
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.
Willoughby
Jane E
JE
Transcription Laboratory, Cancer Research United Kingdom London Research Institute, Lincoln's Inn Fields Laboratories, London, United Kingdom.
Costello
Patrick S
PS
Nicolas
Robert H
RH
Robinson
Nicholas J
NJ
Stamp
Gordon
G
Powrie
Fiona
F
Treisman
Richard
R
D000818:Animals; D000943:Antigens, Differentiation; D049109:Cell Proliferation; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050808:ets-Domain Protein Elk-4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D048490:raf Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000943:Antigens, Differentiation; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C494194:Elk4 protein, mouse; D050808:ets-Domain Protein Elk-4; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases