TGF-beta 1 regulates antigen-specific CD4+ T cell responses in the periphery

J Immunol. 2007 Jul 1;179(1):71-9. doi: 10.4049/jimmunol.179.1.71.

Abstract

T cell expansion typically is due to cognate interactions with specific Ag, although T cells can be experimentally activated through bystander mechanisms not involving specific Ag. TGF-beta1 knockout mice exhibit a striking expansion of CD4+ T cells in the liver by 11 days of age, accompanied by CD4+T cell-dependent necroinflammatory liver disease. To examine whether hepatic CD4+T cell expansion in TGF-beta1(-/-) mice is due to cognate TCR-peptide interactions, we used spectratype analysis to examine the diversity in TCR Vbeta repertoires in peripheral CD4+T cells. We reasoned that Ag-nonspecific T cell responses would yield spectratype profiles similar to those derived from control polyclonal T cell populations, whereas Ag-specific T cell responses would yield perturbed spectratype profiles. Spleen and liver CD4+T cells from 11-day-old TGF-beta1(-/-) mice characteristically exhibited highly perturbed nonpolyclonal distributions of TCR Vbeta CDR3 lengths, indicative of Ag-driven T cell responses. We quantitatively assessed spectratype perturbation to derive a spectratype complexity score. Spectratype complexity scores were considerably higher for TGF-beta1(-/-) CD4+ T cells than for TGF-beta1(+/-) CD4+T cells. TCR repertoire perturbations were apparent as early as postnatal day 3 and preceded both hepatic T cell expansion and liver damage. By contrast, TGF-beta1(-/-) CD4+ single-positive thymocytes from 11-day-old mice exhibited normal unbiased spectratype profiles. These results indicate that CD4+ T cells in TGF-beta1(-/-) mice are activated by and respond to self-Ags present in the periphery, and define a key role for TGF-beta1 in the peripheral regulation of Ag-specific CD4+ T cell responses.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • Autoimmune Diseases / prevention & control
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / pathology
  • Epitopes, T-Lymphocyte / biosynthesis
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology*
  • Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
  • Homeostasis / genetics
  • Homeostasis / immunology
  • Liver / immunology
  • Liver / metabolism
  • Liver / pathology
  • Liver Diseases / genetics
  • Liver Diseases / immunology
  • Liver Diseases / prevention & control
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Receptors, Antigen, T-Cell, alpha-beta / biosynthesis
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / immunology
  • Thymus Gland / metabolism
  • Transcription, Genetic / immunology
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / physiology*

Substances

  • Epitopes, T-Lymphocyte
  • Receptors, Antigen, T-Cell, alpha-beta
  • Transforming Growth Factor beta1