T cells are important regulators of cellular immunity. Trauma impairs T cell function, resulting in sepsis. A better understanding of the events leading to T cell suppression is required. In the previous project period, we found that hypertonic saline (HS) restores T cell function by inducing the release of cellular ATP and by activation of P2X-type purinergic ATP receptors. Recently, we found that stimulation of T cell in general, even under normal physiological conditions, also induces ATP release and that hitherto unknown autocrine purinergic signaling mechanisms regulate T cell function. We identified the molecules that facilitate ATP release (pannexin-1) and the receptors activated by ATP (P2X1 and P2X4). These molecules accumulate at the immune synapse, forming an excitatory purinergic signaling apparatus that initiates T cell activation. After T cell activation is completed, A2a receptors translocate to the immune synapse where they terminate T cell activation. Trauma disrupts these endogenous autocrine purinergic signaling systems, resulting in T cell dysfunction, immunosuppression, and sepsis. We will define the systems that regulate T cells in normal conditions, how trauma distorts these systems, and how therapeutic interventions improve T cell function.
Aim 1) Purinergic signaling systems that regulate T cells under normal conditions: In this section, we will focus on the excitatory and inhibitory autocrine purinergic signaling mechanisms that initiate and then terminate T cell activation under normal physiological conditions. We will study upstream triggers of ATP release, the intracellular source of ATP, and the spatiotemporal mechanisms that orchestrate excitatory and inhibitory purinergic signaling events at the immune synapse.
Aim 2) Mechanisms by which trauma alters purinergic signaling in T cells: We will study with animal models and blood samples from trauma patients how injury impairs the purinergic signaling systems of T cells and whether defective assembly or the malfunction of these purinergic signaling systems contributes to post- traumatic T cell suppression.
Aim 3) Therapeutic approaches to restore T cell function after trauma: In this section we will use animal models of shock and sepsis to investigate whether therapeutic strategies aimed at purinergic signaling defects can overcome T cell suppression, restore immune competence, and reduce the risk of post-traumatic sepsis. We anticipate that the proposed work will reveal important new insights into the mechanisms by which purinergic signaling regulates T cell function and how trauma compromises these signaling mechanisms, resulting in T cell dysfunction and post-traumatic sepsis. Our proposed work may lead to novel therapeutic strategies that reduce the risk of sepsis and that may also benefit patients with other immune disorders.
Purinergic regulation of T cells - Post-traumatic T cell dysfunction and immunosuppression are poorly understood clinical problems that are leading causes of morbidity and mortality in critically ill patients. We have recently discovered that ATP release and autocrine feedback via ATP and adenosine (purinergic) receptors are fundamental processes that are necessary for proper T cell activation. However, trauma impairs these autocrine purinergic signaling systems, resulting in T cell dysfunction, immunosuppression, and an increased risk of post-traumatic complications. We found that purinergic signaling mechanisms are promising pharmacological targets to prevent T cell dysfunction and post-traumatic immunosuppression. We therefore propose to investigate the autocrine and paracrine purinergic signaling mechanisms that regulate normal T cell function and how disruptions of these mechanisms by trauma lead to T cell dysfunction. Our ultimate objective is to identify therapeutic strategies to restore T cell function after trauma.
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|Ledderose, Carola; Bao, Yi; Kondo, Yutaka et al. (2016) Purinergic Signaling and the Immune Response in Sepsis: A Review. Clin Ther 38:1054-65|
|Ledderose, Carola; Bao, Yi; Ledderose, Stephan et al. (2016) Mitochondrial Dysfunction, Depleted Purinergic Signaling, and Defective T Cell Vigilance and Immune Defense. J Infect Dis 213:456-64|
|Ledderose, Carola; Woehrle, Tobias; Ledderose, Stephan et al. (2016) Cutting off the power: inhibition of leukemia cell growth by pausing basal ATP release and P2X receptor signaling? Purinergic Signal 12:439-51|
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