• Thilipan Thaventhiran, Naif Alhumeed, Han X A Yeang, Swaminathan Sethu, Jocelyn S Downey, Ahmad F Alghanem, Adedamola Olayanju, Emma L Smith, Michael J Cross, Steven D Webb, Dominic P Williams, Adrian Bristow, Christina Ball, Richard Stebbings, and Jean G Sathish.
• a Medical Research Council Centre for Drug Safety Science and Department of Molecular and Clinical Pharmacology ; University of Liverpool ; Liverpool , UK.
• MAbs. 2014 Jan 1; 6 (5): 1290-9.

AbstractThe CD28 superagonist (CD28SA) TGN1412 was administered to humans as an agent that can selectively activate and expand regulatory T cells but resulted in uncontrolled T cell activation accompanied by cytokine storm. The molecular mechanisms that underlie this uncontrolled T cell activation are unclear. Physiological activation of T cells leads to upregulation of not only activation molecules but also inhibitory receptors such as PD-1. We hypothesized that the uncontrolled activation of CD28SA-stimulated T cells is due to both the enhanced expression of activation molecules and the lack of or reduced inhibitory signals. In this study, we show that anti-CD3 antibody-stimulated human T cells undergo time-limited controlled DNA synthesis, proliferation and interleukin-2 secretion, accompanied by PD-1 expression. In contrast, CD28SA-activated T cells demonstrate uncontrolled activation parameters including enhanced expression of LFA-1 and CCR5 but fail to express PD-1 on the cell surface. We demonstrate the functional relevance of the lack of PD-1 mediated regulatory mechanism in CD28SA-stimulated T cells. Our findings provide a molecular explanation for the dysregulated activation of CD28SA-stimulated T cells and also highlight the potential for the use of differential expression of PD-1 as a biomarker of safety for T cell immunostimulatory biologics.

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