IFN-gamma regulation in anti-CD4 antibody-induced T cell unresponsiveness

J Am Soc Nephrol. 2004 Mar;15(3):695-703. doi: 10.1097/01.asn.0000115523.50962.c0.

Abstract

The anti-rat CD4 mAb RIB5/2 is very potent in inducing allospecific tolerance in vivo. It is interesting that the unresponsiveness is breakable by exogenous IL-2 applied during the induction phase of tolerance. The molecular mechanisms underlying anti-CD4 antibody-mediated inhibition of allospecific T cell activation and how this is antagonized by exogenous IL-2 were investigated. Anti-CD4 treatment, in vivo and in vitro, completely abrogated IL-2 production by alloreactive T cells. In contrast, anti-CD4-treated alloactivated T cells showed similar IFN-gamma mRNA expression as untreated alloactivated T cells but did not secrete any protein. Thus, the anti-CD4 antibody cannot prevent IFN-gamma mRNA expression but is interfering with posttranscriptional mechanisms that control IFN-gamma production during alloactivation of T cells. Addition of IL-2 but not IL-15 to anti-CD4-treated alloactivated T cells restored IFN-gamma protein production without leading to enhanced IFN-gamma mRNA expression. Further investigations revealed a diminished activation of translation initiation factor eIF2alpha in anti-CD4-treated T cells, which was restored by exogenous IL-2. As activated eIF2alpha is essential for the translation of IFN-gamma mRNA, the results may explain the reversibility of anti-CD4-induced unresponsiveness by exogenous IL-2. Furthermore, these results not only shed further light onto the molecular mechanisms of tolerance induction but also reveal the possible weaknesses of anti-CD4 antibody-induced unresponsiveness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • CD4 Antigens / immunology*
  • Cells, Cultured
  • Interferon-gamma / biosynthesis*
  • Interferon-gamma / genetics
  • Interleukin-2 / genetics
  • Interleukin-2 / physiology*
  • Interleukin-5 / physiology
  • Kidney Transplantation / immunology*
  • Lymphocyte Activation
  • RNA, Messenger / genetics
  • Rats
  • Rats, Inbred Lew
  • Rats, Inbred WF
  • T-Lymphocytes / immunology*

Substances

  • Antibodies, Monoclonal
  • CD4 Antigens
  • Interleukin-2
  • Interleukin-5
  • RNA, Messenger
  • Interferon-gamma