Scurfin (FoxP3) controls T-dependent immune responses in vivo through regulation of CD4+ T cell effector function

J Immunol. 2003 Aug 1;171(3):1216-23. doi: 10.4049/jimmunol.171.3.1216.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adoptive Transfer
  • Agammaglobulinemia / blood
  • Agammaglobulinemia / genetics
  • Agammaglobulinemia / immunology
  • Animals
  • Antigens, T-Independent / administration & dosage
  • Antigens, T-Independent / immunology
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / metabolism
  • B-Lymphocyte Subsets / transplantation
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / transplantation
  • CD40 Ligand / biosynthesis
  • Cells, Cultured
  • Cytokines / antagonists & inhibitors
  • Cytokines / biosynthesis
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Down-Regulation / genetics
  • Down-Regulation / immunology
  • Female
  • Forkhead Transcription Factors
  • Haptens
  • Hemocyanins / administration & dosage*
  • Hemocyanins / immunology*
  • Immunoglobulin G / biosynthesis
  • Immunoglobulin M / biosynthesis
  • Lymphopenia / genetics
  • Lymphopenia / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / transplantation

Substances

  • Antigens, T-Independent
  • Cytokines
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Haptens
  • Immunoglobulin G
  • Immunoglobulin M
  • Rag2 protein, mouse
  • V(D)J recombination activating protein 2
  • trinitrophenyl keyhole limpet hemocyanin
  • CD40 Ligand
  • Hemocyanins