Friday, May 9, 2025
5/9/2025
T Cell Receptor Mediated T Cell Activation in Neonatal and Pediatric Sepsis - Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. children account for half of worldwide sepsis mortality. Neonatal and pediatric sepsis has different clinical characteristics when compared to adult sepsis – indeed the adult sepsis definition is not currently applied to children – but limited research has focused on the immunologic differences in the response to sepsis over age. Herein, we propose to use the natural development of T cell memory as a natural experimental variable to provide insight into how T cell memory influences sepsis-associated organ dysfunction. We hypothesize that, in dysregulated inflammation, hyperactivated APCs overexpress co-ligands that promote T cell receptor (TCR)- mediated activation of memory T cells, directing aberrant host responses and amplifying innate immune activity and organ dysfunction in sepsis and other severe inflammatory diseases. Angiotensin II signaling modulates these interactions. We are uniquely positioned to study T cell memory responses to sepsis over age – and we posit that the dysregulated T cell-APC interactions that we have found increase in prevalence and influence in directing the response to sepsis as we age. Specifically, we hypothesize that the T cell receptor activation threshold is influenced by sepsis and age – and that this threshold may be a key in understanding sepsis. The principal investigator has demonstrated that T cell memory responses promote both innate immunity and organ dysfunction in previous work. The global hypothesis of our work is that, in sepsis, altered host responses that cause organ dysfunction may be characterized by dysregulated and dysfunctional interactions between immune cells, primarily driven by memory TCR activation. We propose herein to use comparisons between human neonates with sepsis and pediatric and adult sepsis patients to understand how T cell memory and sepsis affect T cell-APC interactions and TCR activation. We will further pursue work to understand how other circulating factors in sepsis, specifically components of the renin-angiotensin-aldosterone, are affected by age and affect TCR-activation. TCR signal response effects on sepsis are not well understood and represents a clear gap in our understanding of human sepsis pathophysiology – we aim to address this gap in our current proposal.
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