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

T cells play a central role in regulating the immune system. Impaired T cell function renders the host susceptible to infections. Trauma, shock, and burn injuries impair T cell function resulting in infections and sepsis that are major causes of deaths among trauma patients. The core focus of this proposal is to define the signaling mechanisms by which trauma impairs T cell function.Specifically, I will focus on the newly discovered purinergic signaling system that regulates T cell function under normal physiological circumstances, and on its role in T cell suppression. In healthy subjects, T cell stimulation induces the release of cellular ATP. Following its release, ATP must stimulate purinergic receptors on the cell surface to induce appropriate T cell activation. Adenosine, a metabolite of ATP, has been shown to play a role in suppressing immune responses. The working hypothesis to be tested in this project is that trauma alters these purinergic signaling processes and thereby suppresses T cell function.The first part of the project will focus on the open questions as to how excitatory purinergic signaling triggers T cell activation and how inhibitory purinergic signaling processes modulate T cell responses. Specifically, I will focus on the upstream events that cause ATP release, the mechanisms that break down ATP to adenosine outside the cell, and the spatiotemporal sequence of events that orchestrate the excitatory and inhibitory purinergic signaling mechanisms that regulate T cell function.The second part of the project will focus on the effect of trauma on these purinergic signaling systems. Using in vitro models of immunosuppression as well as T cells from actual trauma patients, I will investigate how injury impairs the purinergic signaling systems of T cells, and whether defective assembly or the malfunction of these purinergic signaling systems contribute to post-traumatic T cell suppression.The ultimate goal of this work is to find new approaches to improve T cell function and prevent septic complications in trauma patients.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Wolfgang Junger, Ph.D.