UBC Theses and Dissertations
Metabolic regulation of the anti-helminth CD4+ T cell response Heieis, Graham Anthony
Cellular metabolism is intricately linked to the activation and effector function of CD4+ T cells. Activation triggers an increase in glycolysis, which is thought to fuel the necessary biosynthetic demands of growth and proliferation. Recent work suggests that glycolytic activity further coordinates distinct functions in different T helper subsets. Thus far, however, little has been elucidated about the regulation of metabolism in Th2 cells. Using in vitro cultures and in vivo infection models, I compared glycolysis in Th1 and Th2 cells generated from cytokine-reporter mice. This revealed that Th2 cells from infected mice maintain a low glycolytic rate that more closely resembles that of naïve T cells. I hypothesized Th2 cells may be metabolically suppressed by helminths during infection, and therefore tested the capability of purified helminth products to alter glycolysis of in vitro polarized Th2 cells. Cytokine production was inhibited, but an effect on glycolysis could not be consistently demonstrated. However, signalling through the metabolic regulator, mTOR, was reduced in T cells from helminth infected mice compared to controls, supporting the possibility of metabolic modulation in vivo. I questioned whether Th2 cell glycolysis was regulated after exiting the lymph node. By assessing Th2 cell metabolism from the effector site, I discovered that fatty acid metabolism, and not glycolysis, was upregulated in the peripheral tissue. Fatty acid uptake was enhanced in cells expressing the IL-33 receptor, ST2. These cells highly co-expressed programmed death protein 1 (PD-1), a known regulator of T cell metabolism. Hence, I predicted that PD-1 signalling promotes ST2 expression in the tissue. Accordingly, ex vivo stimulation of sorted Th2 cells through PD-1 increased ST2 expression. From these data I propose that PD-1 signalling overcomes a metabolic checkpoint to permit alarmin-responsiveness and tissue-localized cytokine production. Overall, these findings illustrate Th2 metabolism is dynamic in vivo, and that fatty acid metabolism is the predominant pathway regulated during effector differentiation. Importantly, these results argue that immunometabolism data from in vitro systems may not be applicable in vivo. Continuing to understand in vivo Th2 cell metabolism could be pertinent to the future design of anti-helminth treatments, which are urgently needed.
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