The c-Rel Transcription Factor Controls Metabolism and Proliferation of Human T Cells / George S. Luo.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Luo, George S., author.

Contributor:

Chen, Youhai H., degree supervisor.

Bi, Erfei, degree committee member.

Guo, Wei, degree committee member.

Hancock, Wayne W., degree committee member.

Ricciardi, Robert P., degree committee member.

Wells, Andrew D., degree committee member.

University of Pennsylvania. Department of Biology, degree granting institution.

Language:

English

Subjects (All):

Penn dissertations--Biology.

Biology--Penn dissertations.

Local Subjects:

Penn dissertations--Biology.

Biology--Penn dissertations.

Physical Description:

ix, 89 leaves : illustrations ; 29 cm

Production:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2017.

Summary:

Environment-driven metabolic reprogramming is a persistent feature throughout the life cycle of T cells and is essential for their normal development and functioning. Consequently, abnormal metabolic adaptation underpins a number of human diseases, including cancer. Although the great metabolic adaptation potential helps T cells to survive nutrient-restricted regions in the periphery and fulfill their duty in immune surveillance and other functions, it also helps T cell derived tumor cells to survive the nutrient-deprived tumor microenvironment, thus making them more resilient and difficult to combat. It has long been shown that cancer cells exhibit a metabolic shift from oxidative phosphorylation to aerobic glycolysis, a phenomenon known as the Warburg effect. A similar metabolic shift is also observed in activated T cells, suggesting a common mechanism between immune activation and tumorigenesis. However, this mechanism remains to be elucidated. The lymphoid-specific NF-κB family transcription factor c-Rel is a key regulator of B- and T-cell activation and immune response, and has been implicated in a number of hematopoietic cancers. To investigate the function and regulation of c-Rel in human T cells, we generated c-Rel knockout human T cell line Jurkat cells using the CRISPR/Cas9 system and analyzed the resulting phenotype. Our results revealed that c-Rel is a key metabolic regulator that facilitates T cell growth and proliferation by regulating energy metabolism to promote glycolysis and mitochondrial respiration. Disruption of c-Rel in Jurkat cells leads to dramatic reduction in cell growth and broad defects in both glycolysis and mitochondrial respiration. These metabolic defects are also observed in primary T cells isolated from c-Rel knockout mice, demonstrating c-Rel's critical role in regulating T cell metabolism across species. Moreover, c-Rel knockout (KO) cells failed to adapt to nutrient-limited conditions and lost their proliferative capacity. Mechanistically, c-Rel is upregulated in response to nutrient stress and drives the expression of c-Myc--a potentiator of many genes in the glycolytic and mitochondrial respiratory pathway. Overexpression of c-Myc in c-Rel KO cells compensated for the loss of c-Myc induction under nutrient stress, and reversed the proliferative and metabolic defects. These results establish that c-Rel is a key stress responder and metabolic regulator that maintains cell growth and survival under nutrient stress and promotes the Warburg effect. Thus, strategies targeting c-Rel may provide an effective way to suppress cancer metabolism.

Notes:

Ph. D. University of Pennsylvania 2017.

Department: Biology.

Supervisor: Youhai H. Chen.

Includes bibliographical references.

OCLC:

1334941493