Poster Presentation The Melbourne Immunotherapy Network Winter Symposium 2019

Early memory T cells propagate exhaustion during chronic infection (#109)

Daniel T Utzschneider 1 , Sarah S Gabriel 1 , Axel Kallies 1 2
  1. The University of Melbourne and The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  2. The Walter and Eliza Hall Institute of Medical Research, Parkville

Immunity to chronic viral infections and tumors is tightly associated with ‘exhausted’ T cells, which display loss of effector function and expression of inhibitory receptors, most notably PD-1. Exhausted T cell responses are sustained over long periods by a subset of specialized T cells that retain high proliferative capacity and the ability to self-renew while also displaying hallmarks of T cell exhaustion. Importantly, these ‘exhausted memory’ T cells or TMEX are responsible for the boost of immunity following checkpoint blockade in immunotherapy. Here we show that during the onset of an immune response to a chronic infection, early memory but not effector T cells acquire features of exhaustion, including an epigenetic and transcriptional profile of exhausted T cells. Importantly, this early TMEX population propagates this differentiation pattern by replenishing the effector response with exhausted T cells in a process that depends on the expression of the transcriptional regulator ID3. Overall, we demonstrate that T cell exhaustion is manifested early during T cell activation and show that a specialized population of memory T cells initially acquires and propagates this differentiation pattern.