Naive human T-cells become non-responsive towards anti-TNFα (infliximab) treatment in vitro if co-stimulated through CD28

Abstract

Tumour necrosis factor α (TNFα) inhibitors are widely used successfully as immunomodulatory agents in various autoimmune diseases. They primarily target the direct pro-inflammatory effect of TNFα. They have also been found to be critical for T-cell viability and activation. In this study we evaluated the effect of infliximab treatment under different in vitro stimulatory conditions of naive human cord blood T-cells and adult peripheral blood mononuclear cells (PBMC). PBMC and negatively selected cord blood naive human T-cells were stimulated with αCD3 with or without αCD28 co-stimulation. The role of in vitro infliximab treatment was evaluated in relation to transforming growth factor-β1 (TGF-β1) under the above different stimulatory conditions. Anti-TNFα treatment with infliximab significantly suppressed proliferation of adult and cord blood T-cells (P < 0.013) during suboptimal stimulatory conditions. Infliximab prevented division of naive CD4+ and CD8+ T-cells and consequently also activation induced cell death, which was induced after three cell divisions. Interleukin (IL)-2 secretion was significantly decreased during infliximab treatment of suboptimally stimulated T-cells (P < 0.05) while TGF-β1 levels were unchanged. Strikingly, the anti-proliferative effect of infliximab was overcome by the administration of anti-TGF-β1 or by the addition of exogenous IL-2. Interestingly, CD28 mediated co-stimulation restored the proliferative response in a dose-responsive manner during infliximab treatment. Finally, exogenous TNFα administration during suboptimal stimulation reduced the inhibitory effect of TGF-β1 upon proliferation (P < 0.03). These results demonstrate that anti-TNFα treatment is primarily working upon T cells under low stimulatory conditions and probably through TGF-β1. © 2008 The Authors.