Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Taku Kambayashi

Abstract

Type 2 helper T cells (Th2) are beneficial for orchestrating protective immune responses against helminths but can also be pathogenic in settings of allergy and asthma. Weak TCR-mediated extracellular signal-regulated kinase (ERK) signals are thought to promote Th2 differentiation in vitro. However, it was unclear whether selective enhancement of specific TCR-mediated signal transduction pathways could suppress Th2 differentiation in vitro and block Th2 inflammation in vivo in a polyclonal setting. The lipid molecule diacylglycerol (DAG) is the main driver of TCR-mediated ERK activation. Here, we demonstrate that T cells lacking DAG kinase-ζ (DGKζ), a negative regulator of DAG, display impaired Th2 differentiation in vitro. Accordingly, mice lacking DGKζ exhibited decreased type 2 airway inflammation and were almost completely resistant to airway hyperresponsiveness (AHR) in vivo in an OVA-induced mouse model of allergic asthma. Surprisingly, we found that the mechanisms by which DGKζ protected against airway inflammation and AHR were separable. Conditional deletion of DGKζ in T cells led to decreased type 2 airway inflammation with no attenuation of AHR. In contrast, conditional deletion of DGKζ in airway smooth muscle cells led to diminished AHR with no attenuation of airway inflammation. Mechanistically, T-cell specific enhancement of ERK signaling was sufficient to diminish Th2 differentiation in vitro and attenuate type 2 airway inflammation with no changes in AHR in vivo. These data demonstrate that specific enhancement of DAG signaling downstream of the TCR is sufficient to attenuate Th2 differentiation in an ERK-dependent manner. Furthermore, our findings reveal that the inflammatory and AHR components of asthma are not as interdependent as generally believed.

Additionally, we also demonstrate a novel role for DGKζ in regulating protease allergen-mediated type 2 airway inflammation. We found that global but not hematopoietic-specific ablation of DGKζ was sufficient to protect from papain-induced airway inflammation. Further analysis revealed that protection from papain in the absence of DGKζ might be potentially due to an impairment in IL-33 production/release in response to papain. Collectively, this thesis highlights that DGKζ plays immunomodulatory roles during Th2 differentiation and in the non-hematopoietic compartments to regulate type 2 immune-mediated disease.

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

Share

COinS