Scurfin (FoxP3) controls T-dependent immune responses in vivo through regulation of CD4+ T cell effector function.
Scurfin, the protein product of the FoxP3 gene, is a forkhead-family transcription factor that negatively regulates T cell function. Mice carrying a loss-of-function mutation in FoxP3 (scurfy mice) present with fatal autoimmune-like disease caused by hyperresponsive CD4(+) T cells. Mice that overexpress scurfin (FoxP3 Tg mice) possess fewer mature T cells with reduced functional capabilities compared with normal littermate control mice. We analyzed the ability of CD4(+) T cells and B cells from FoxP3 Tg mice to respond to a T-dependent Ag and found that immunized FoxP3 Tg mice displayed reduced total and Ag-specific serum Ig and disorganized splenic architecture. However, when cultured in vitro, FoxP3 Tg B cells responded normally, suggesting that the poor Ab response was a result of defective T cell help in vivo. When challenged, CD4(+) T cells from FoxP3 Tg mice display reduced up-regulation of CD40 ligand and fewer IFN-gamma-producing cells. Overall, these findings show that overexpression of scurfin reduces T cell responses in vivo such that CD4(+) T cells cannot provide help to B cells during a T cell-dependent Ab response.
Kasprowicz
Deborah J
DJ
Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
Smallwood
P Scott
PS
Tyznik
Aaron J
AJ
Ziegler
Steven F
SF
D019264:Adoptive Transfer; D000361:Agammaglobulinemia / Q000097:blood / Q000235:genetics / Q000276:immunology; D000818:Animals; D000955:Antigens, T-Independent / Q000008:administration & dosage / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D023201:CD40 Ligand / Q000096:biosynthesis; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors; D006241:Haptens; D006433:Hemocyanins / Q000008:administration & dosage* / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
D000955:Antigens, T-Independent; D016207:Cytokines; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006241:Haptens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; C054401:trinitrophenyl keyhole limpet hemocyanin; D023201:CD40 Ligand; D006433:Hemocyanins