Role of purinergic signaling in post-traumatic T cell suppression

• Applicant: Dr. Carola Ledderose
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Anaesthesiology ; Immunology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 240036772

• Final Report Year: 2015

Final Report Abstract

Sepsis is a leading cause of death in intensive care patients and a common complication in patients suffering from severe trauma or burn injuries. T cells play a central role in the regulation of the immune response. In patients with sepsis, T cell function is suppressed and renders the organism susceptible to hospital-acquired secondary infection; however, the pathogenic mechanisms leading to T cell suppression are not well understood. The overall aim of this project has been to explore the mechanisms that impair T cell function in sepsis. Specifically, I focused on the recently discovered purinergic signaling system that is known to regulate T cell activation under normal physiological conditions. Healthy T cells respond to the stimulation of their T cell receptors with the release of adenosine triphosphate (ATP) into the extracellular space. Following its release, ATP stimulates purinergic receptors expressed on the surface of T cells. This feedback is essential for effective functional T cell responses. Investigating the purinergic mechanisms that regulate T cell function under normal conditions, I found that mitochondria play a central role by providing the ATP that fuels this purinergic feedback process. T cell stimulation triggers ATP formation by mitochondria that accumulate at the immune synapse, the contact site between T cells and antigen-presenting cells. Using a novel fluorescence-based live-cell imaging method, I could demonstrate that ATP is released into the synaptic cleft where it stimulates P2X receptors. This promotes cellular calcium influx that up-regulates and perpetuates mitochondrial activity until the T cell response is completed. Interestingly, I discovered that not only stimulated T cells utilize this mechanism. Instead, I found a similar mechanism in unstimulated resting T cells. It keeps T cells alert and enables them to seek and recognize antigens and to quickly mount an appropriate functional response. Importantly, my studies revealed that this standby purinergic signaling system of unstimulated T cells is impaired in patients with sepsis, rendering these patients incapable of mounting adequate functional immune responses to infections. In conclusion, I was able to define a new mechanism that is responsible for T cell suppression in sepsis, suggesting novel therapeutic strategies targeting mitochondrial and purinergic dysfunction to improve T cell function and outcome in sepsis.

Publications

• Mitochondria are gate-keepers of T cell function by producing the ATP that drives purinergic signaling. J Biol Chem 2014 Sep 12;289(37):25936-45
  Ledderose, Carola; Bao, Yi; Lidicky, Markus; Zipperle, Johannes; Li, Linglin; Strasser, Katharina; Shapiro, Nathan I. & Junger, Wolfgang G.
  
• Novel method for real-time monitoring of ATP release reveals multiple phases of autocrine purinergic signalling during immune cell activation. Acta Physiol (Oxf) 2015 Feb;213(2):334-45
  Ledderose, C.; Bao, Y.; Zhang, J. & Junger, W. G.
  
• Mitochondrial dysfunction, depleted purinergic signaling, and defective T cell vigilance and immune defense. J Infect Dis 2015 Jul 6. pii: jiv373
  Ledderose, Carola; Bao, Yi; Ledderose, Stephan; Woehrle, Tobias; Heinisch, Maria; Yip, Linda; Zhang, Jingping; Robson, Simon C.; Shapiro, Nathan I. & Junger, Wolfgang G.