Blocking B7 and CD40 co-stimulatory molecules decreases antiviral T cell activity.

SUMMARY Inhibition of co-stimulatory signals for T cells by interrupting CD80/CD86–CD28 and CD40–CD154 interactions is a promising approach to prevent transplant rejection and to induce graft tolerance. However, this tolerizing treatment might affect T cell reactivity towards all the antigens to which the immune system is exposed during treatment. We addressed the question whether such inhibition of co-stimulatory ligands on human antigen presenting cells (APC) would affect T cell reactivity against a virus. This was tested in an in vitro system with freshly isolated human monocytes transduced with adenovirus (ad) containing either murine interferon-γ (mIFN-γ) or green fluorescent protein (GFP) as marker transgene. T cells co-cultured with transduced monocytes proliferated and produced cytokines. These ‘primed’ T cells had strong antiviral activity as they subsequently killed ad/GFP-transduced monocytes and reduced mIFN-γ accumulation in coculture with ad/mIFN-transduced monocytes. However, if priming had occurred in the presence of blocking anti-CD40/CD80/CD86 MoAbs, generation of this antiviral activity was completely prevented. Moreover, T cells primed in the absence of co-stimulatory cells failed to proliferate upon restimulation with adenovirus-transduced monocytes. The results confirm that co-stimulatory signals from APC are required for efficient induction of antiviral T cell activity and point to a potential infectious risk of blocking co-stimulatory signals.