Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Warren S. Pear


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.


Available to all on Tuesday, January 10, 2023

Files over 3MB may be slow to open. For best results, right-click and select "save as..."