CD4 T cell dysfunction and reprogramming during sepsis

Sepsis remains a major cause of death worldwide (11 million sepsis-related deaths were reported in 2017), and that costs associated with treating septic patients place a large burden on the healthcare industry. Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Early stages of sepsis are marked by hyperinflammation driven by proinflammatory cytokines (i.e., IL-1β, IL-6, IFNγ, and TNF). Patients who survive the acute phase of sepsis display long-term impairments in immune function. This state of chronic immunoparalysis renders sepsis survivors increasingly susceptible to secondary infections. Consequently, there is a desperate need to better understand the cellular and molecular basis of acute sepsis pathophysiology and subsequent immune reprogramming that defines the prolonged immune suppression. CD4 T cells, essential for coordinating the cellular and humoral immune response to a range of pathogens under normal circumstances, are severely depleted during the acute stage of sepsis. The overall number of CD4 T cells gradually recover over time, but their functional capacity remains blunted for many months. For the past 10 years, we have focused our research to pursue the long-term goal of understanding how sepsis impacts the CD4 T cell compartment because of the key role played by CD4 T cells in the overall fitness of the immune system. We will continue our investigation of the cellular and molecular reprogramming of CD4 T cells during sepsis in three interconnected areas of future research: 1) Define the mechanism(s) by which regulatory CD4 T (Treg) cells expand during sepsis; 2) Perform an integrated discovery approach using genomics, proteomics, and metabolomics to elucidate the molecular basis of sepsis pathophysiology and CD4 T cell immunoparalysis; and 3) Determine how intestinal microbiota dysfunction during sepsis affects the magnitude of the cytokine storm and promotes CD4 T cell immunoparalysis and increased incidence of late-onset mortality. We will interrogate samples obtained from multiple cohorts of sepsis patients, as well as from preclinical mouse models of sepsis at the level of Ag-specific CD4 T cell populations. Our preclinical studies will be further strengthened by using a novel mouse model that mimics a critical aspect of human biology – exposure to multiple ongoing and resolved infections trains the immune system for robust responses to new pathogens – and will serve as an important and novel ‘transitional translational’ preclinical bridge between humans and SPF laboratory mice to mechanistically study CD4 T cell dysfunction and reprogramming during sepsis. Addressing these key gaps in knowledge regarding the effect of sepsis on CD4 T cell biology will likely reveal new points of intervention that can be exploited in the future to restore CD4 T cell-mediated immunity, and overall immune fitness, following sepsis.