The amount of scurfin protein determines peripheral T cell number and responsiveness.
In the absence of the recently identified putative transcription factor scurfin, mice develop a lymphoproliferative disorder resulting in death by 3 wk of age from a pathology that resembles TGF-beta or CTLA-4 knockout mice. In this report, we characterize mice that overexpress the scurfin protein and demonstrate that these animals have a dramatically depressed immune system. Mice transgenic for the Foxp3 gene (which encodes the scurfin protein) have fewer T cells than their littermate controls, and those T cells that remain have poor proliferative and cytolytic responses and make little IL-2 after stimulation through the TCR. Although thymic development appears normal in these mice, peripheral lymphoid organs, particularly lymph nodes, are relatively acellular. In a separate transgenic line, forced expression of the gene specifically in the thymus can alter thymic development; however, this does not appear to affect peripheral T cells and is unable to prevent disease in mice lacking a functional Foxp3 gene, indicating that the scurfin protein acts on peripheral T cells. The data indicate a critical role for the Foxp3 gene product in the function of the immune system, with both the number and functionality of peripheral T cells under the aegis of the scurfin protein.
Khattri
R
R
Celltech R&D, Inc., Bothell, WA 98021, USA.
Kasprowicz
D
D
Cox
T
T
Mortrud
M
M
Appleby
M W
MW
Brunkow
M E
ME
Ziegler
S F
SF
Ramsdell
F
F
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000276:immunology; D006651:Histocytochemistry; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D018655:Lymphocyte Count; D007959:Lymphocyte Culture Test, Mixed; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019076:Transgenes / Q000276:immunology
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse