Immune checkpoint blockade (ICB) targeting the inhibitory receptors CTLA-4, PD-1 and PD-L1, the major PD-1 ligand, have revolutionized cancer therapy ( 1, 2). These so-called immune checkpoints represent attractive therapeutic targets in attempts to manipulate immune responses in autoimmune diseases, virus infections or tumors. T cell activation is initiated by antigen recognition via the TCR complex and regulated by signals generated by co-stimulatory and co-inhibitory receptors. Furthermore, experiments with T cell reporter cells and primary T cells demonstrate that HVEM antibodies can augment T cell responses by concomitantly acting as checkpoint inhibitors and co-stimulation agonists. Stimulation of primary human T cells in presence of HVEM ligands indicated a weak costimulatory capacity of HVEM potentially owed to its in cis engagement by BTLA. Intriguingly, our data indicate that BTLA mediated inhibition is not impaired in this heterodimeric complex, suggesting a dominant role of BTLA co-inhibition. In line with earlier reports, we observed that in cis interaction of BTLA and HVEM prevented HVEM co-stimulation by ligands on surrounding cells. Co-expression with LIGHT or CD160, but not with BTLA, induced strong constitutive signaling via HVEM. Here, we have used T cell reporter systems to dissect the complex interplay of HVEM with BTLA and its additional ligands LIGHT and CD160. BTLA and HVEM have both been implicated in the regulation of human T cell responses, but their role is complex and incompletely understood. The engagement of the herpesvirus entry mediator (HVEM, TNFRSF14) by the B and T lymphocyte attenuator (BTLA) represents a unique interaction between an activating receptor of the TNFR-superfamily and an inhibitory receptor of the Ig-superfamily. 3Team Immunity and Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068 Centre National de la Recherche Scientifique (CNRS), UMR7258 Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France.2Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.1Division of Immune Receptors and T Cell Activation, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.Claire Battin 1, Judith Leitner 1, Petra Waidhofer-Söllner 2, Katharina Grabmeier-Pfistershammer 2, Daniel Olive 3 and Peter Steinberger 1*
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