IFN-γ Regulation in Anti-CD4 Antibody–Induced T Cell Unresponsiveness

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-γ mRNA expression as untreated alloactivated T cells but did not secrete any protein. Thus, the anti-CD4 antibody cannot prevent IFN-γ mRNA expression but is interfering with posttranscriptional mechanisms that control IFN-γ production during alloactivation of T cells. Addition of IL-2 but not IL-15 to anti-CD4–treated alloactivated T cells restored IFN-γ protein production without leading to enhanced IFN-γ mRNA expression. Further investigations revealed a diminished activation of translation initiation factor eIF2α in anti-CD4–treated T cells, which was restored by exogenous IL-2. As activated eIF2α is essential for the translation of IFN-γ 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.