The ability to develop and sustain memory CD8 T cells post-infection or vaccination is a hallmark of the adaptive immune response and the basis for protective vaccination against infectious disease or in cancer immunotherapy. Since the degree of protection to infection depends on the functional characteristics (quality) and number (quantity) of memory CD8 T cells present at the time of antigen (Ag) re-exposure, understanding the mechanisms that govern nave-to-memory CD8 T cell differentiation and long-term maintenance of the memory CD8 T cell pool are critical for achieving maximal protection. The outcome of viral or bacterial infections is determined by a series of complex interactions between the pathogen and infected host. Among these interactions the immune status of the host at the time of infection can have a major impact in the host susceptibility to disease. Polymicrobial sepsis represents a leading cause of death in most intensive care units, and patients who survive sepsis often display severely compromised immune function with deficits in innate and adaptive immune responses. One hallmark of the general immune suppression observed during polymicrobial sepsis is diminished T cell immunity. Consequently, septic patients and sepsis survivors are highly susceptible to new or previously encountered infections that are readily controlled by T cells when a normal, functioning immune system is present. In this regard, our recent papers revealed that sepsis significantly compromises the host's ability to mount optimal CD8 T cell responses to newly introduced Ag presented in the context of systemic and localized model infections. Our data in these publications also revealed a previously unappreciated role for sepsis in shaping the quantity and functionality of infection- or vaccine-induced pre-existing memory CD8 T cells. However, the extent of sepsis-induced changes the nave and memory CD8 T cell pool and mechanisms that control their recovery, long-term maintenance and differentiation as well as potential therapeutic interventions to restore number and/or function of nave and memory CD8 T cells in sepsis survivors are currently unknown. Thus, our long-term goal is to fully understand the functional consequences imposed on nave and pre-existing memory CD8 T cell populations following sepsis induction. Our central hypothesis is that sepsis-induced apoptosis of Ag-specific nave and/or memory CD8 T cells leads to long-lasting deleterious changes in the composition and/or function of CD8 T cell responses that ultimately result in diminished CD8 T cell responses to newly or previously encountered Ag delivered in the context of localized and systemic infections. We will address our long-term goal with the following specific aims:
Aim 1 - Define the regulatory role of dendriti cells in sepsis-induced impairment of CD8 T cell immunity to newly introduced antigens.
Aim 2 - Determine the extent to which CD8 T cell intrinsic factors control primary CD8 T cell responses after sepsis.
Aim 3 - Determine the impact of sepsis on maintenance and function of pre-existing memory CD8 T cell responses.
Polymicrobial sepsis represents a leading cause of death in most intensive care units, and patients who survive severe sepsis often display severely compromised immune function with deficits in innate and adaptive immune responses. One hallmark of the general immune suppression observed during polymicrobial sepsis is diminished T cell immunity. There are clear knowledge gaps in our understanding of how, when and the extent to which sepsis-associated impairment of CD8 T cell-mediated immunity recovers and understanding the mechanisms behind sepsis-induced changes in the homeostasis of nave and pre-existing memory CD8 T cell responses will lead to new approaches aimed at restoring adaptive immunity in individuals surviving sepsis.
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