CD4+CD25+ regulatory T cells suppress allograft rejection mediated by memory CD8+ T cells via a CD30-dependent mechanism

J Clin Invest. 2004 Jan;113(2):310-7. doi: 10.1172/JCI19727.

Abstract

CD4(+)CD25(+) regulatory T (Treg) cells suppress naive T cell responses, prevent autoimmunity, and delay allograft rejection. It is not known, however, whether Treg cells suppress allograft rejection mediated by memory T cells, as the latter mount faster and stronger immune responses than their naive counterparts. Here we show that antigen-induced, but not naive, Treg cells suppress allograft rejection mediated by memory CD8(+) T cells. Suppression was allospecific, as Treg cells induced by third-party antigens did not delay allograft rejection. In vivo and in vitro analyses revealed that the apoptosis of allospecific memory CD8(+) T cells is significantly increased in the presence of antigen-induced Treg cells, while their proliferation remains unaffected. Importantly, neither suppression of allograft rejection nor enhanced apoptosis of memory CD8(+) T cells was observed when Treg cells lacked CD30 or when CD30 ligand-CD30 interaction was blocked with anti-CD30 ligand Ab. This study therefore provides direct evidence that pathogenic memory T cells are amenable to suppression in an antigen-specific manner and identifies CD30 as a molecule that is critical for the regulation of memory T cell responses.

Publication types

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

MeSH terms

  • Animals
  • Antigens / biosynthesis
  • Antigens / chemistry
  • Apoptosis
  • Bromodeoxyuridine / pharmacology
  • CD4 Antigens / biosynthesis
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Division
  • Cytokines / metabolism
  • Graft Rejection
  • Homozygote
  • Hyaluronan Receptors / biosynthesis
  • Immunologic Memory
  • Immunophenotyping
  • In Situ Nick-End Labeling
  • Ki-1 Antigen / biosynthesis*
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Receptors, Interleukin-2 / biosynthesis*
  • Spleen / cytology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism
  • Time Factors

Substances

  • Antigens
  • CD4 Antigens
  • Cytokines
  • Hyaluronan Receptors
  • Ki-1 Antigen
  • Ligands
  • Receptors, Interleukin-2
  • Bromodeoxyuridine