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Differentiation into Effector Cells with Distinct Memory Fates: Contributions of Viral Dose and Functional Avidity

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abstract
Generating and maintaining a robust CD8+ T cell response in the face of high viral burden is vital for host survival. By the peak of the CD8+ T cell response, the effector cell pool consists of a heterogeneous population of cells that includes both those with an increased propensity to become long-lived memory cells (memory precursor effector cells, MPEC) and those that are terminally differentiated cells (short-lived effector cells, SLEC). Balancing the differentiation of effectors along the memory precursor effector cell (MPEC) vs. short-lived effector cell (SLEC) pathways is critical in controlling the outcome of virus infection with regard to clearance and establishing protection. While recent studies have identified several factors that have the capacity to regulate effector CD8+ T cell differentiation, e.g. inflammatory cytokines, we are far from a complete understanding of how cells choose the MPEC vs. SLEC fate following infection. Work presented here examines two factors; functional avidity and viral dose and how they contribute to effector cell differentiation. The data presented here show that at the peak of the effector response generated following poxvirus or LCMV infection, SLEC were of higher functional avidity than their MPEC counterpart. Over time however, SLEC exhibited a decrease in peptide sensitivity in mice infected with VV but not LCMV. The decrease in functional avidity in SLEC was independent of CD8 modulation or the amount of antigen receptor expressed by the T cell. Instead the loss in sensitivity was correlated with decreased ZAP-70 and Lck expression as well as their phosphorylated products, both important molecules in T cell receptor membrane proximal signaling. These results highlight the potential contribution of avidity in the differentiation and evolution of the T cell effector response following viral infection. Also, we modulated the infectious dose of the poxvirus vaccinia virus as an approach to modulate the environment present during activation and expansion of virus-specific effector cells. Surprisingly, in the face of a high virus burden, SLEC generation was decreased. This was the result of increased nTregs generated by high viral burden as depletion of these cells restored SLEC. Our data suggest nTregs modulation of differentiation occurs via competition for IL-2 during the late expansion period, as opposed to the time of T cell priming. These findings support a novel model wherein modulation of the nTregs response as a result of high viral burden regulates late stage SLEC generation.
subject
Differentiation
Memory precursor effector cells
MPEC
regulatory T cells
Short-lived effector cells
SLEC
contributor
Amoah, Samuel (author)
Alexander-Miller, Martha (committee chair)
Grayson, Jason (committee member)
Parks, Griffith (committee member)
Mishra, Nilamadhab (committee member)
Hiltbold-Schwarz, Elizabeth (committee member)
date
2012-06-12T08:36:01Z (accessioned)
2014-06-12T08:30:08Z (available)
2012 (issued)
degree
Microbiology & Immunology (discipline)
embargo
2014-06-12 (terms)
identifier
http://hdl.handle.net/10339/37292 (uri)
language
en (iso)
publisher
Wake Forest University
title
Differentiation into Effector Cells with Distinct Memory Fates: Contributions of Viral Dose and Functional Avidity
type
Dissertation

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