Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Warren S. Pear

Abstract

In chronic disease, persistent antigen stimulation results in a gradual loss in function of the exhausted T cell (TEX) pool, and a subsequent loss of pathogen control. Identifying factors that can enhance or sustain TEX function is thus critically important for establishing more durable responses to chronic pathogens. Additionally, T cell effector differentiation is poorly understood in the context of T cell exhaustion but targeting effector-like responses may provide additional strategies for controlling persistent viral infections. Using the LCMV mouse model of infection, we identify Tribbles Pseudokinase 1 (Trib1) as a central regulator of the T cell effector response to chronic infection. Within the exhausted setting of chronic LCMV infection, loss of Trib1 enforced an effector phenotype, which enhanced and sustained effector-associated T cell numbers and T cell function and improved viral control. Using single cell transcriptional profiling we revealed that Trib1 is a central regulator of effector vs. exhausted CD8 T cell programming and differentiation during chronic disease. Specifically, loss of Trib1 led to the sustained expansion of a population of KLRG1+ CD8 T cells that have an elevated cytotoxic signature and low expression of various markers and drivers of T cell exhaustion. These cells were enriched for a program more similar to that of cells responding to an acute infection, and were transcriptionally distinct from exhausted T cell subsets. The Trib1-deficient mouse model offers a unique opportunity to study these effector-like cells throughout a chronic immune response. We also demonstrate an important role for Trib1 in regulating CD4 T cell function during chronic infection and identify both CD4-dependent and CD4-independent roles for Trib1 in regulating CD8 effector responses. Mechanistically, we identified an interaction between Trib1 and the T cell receptor (TCR) signaling activator, MALT1, which disrupted MALT1 signaling complexes. These data support a model of negative feedback regulation whereby Trib1 restrains TCR signaling and downstream function, and identify a link between Trib1 and effector T cell programming and differentiation that can be targeted to improve antiviral immunity.

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