Dissertation
Role of microRNA-155 in CD8+ T cell responses
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2012
DOI:
https://doi.org/10.17918/00000824
Abstract
MicroRNAs (miRNAs) have been described as important regulators of gene expression, mediating their effect either by inhibiting protein translation or by degrading the mRNA transcripts. miRNAs such as miR-155 can influence immune responses by regulating the function of macrophages, dendritic cells, B cells and CD4+ T cells. However, the important role miRNAs play in host immunity and specifically in CD8+ T cell responses is largely unexplored. We show here that miR-155 is highly up-regulated in CD8+ T cells upon activation and during primary responses, while it is down-regulated in central memory and to a lesser extent in effector memory CD8+ T cells. Infection of miR-155 deficient mice with influenza A virus results in decreased anti-viral CD8+ T cell responses and viral clearance. This defect is intrinsic to CD8+ T cells, as miR-155 deficiency in CD8+ T cells greatly reduces in vivo primary and memory responses to influenza A virus and Listeria monocytogenes. In contrast, miR-155 overexpression augments CD8+ T cell responses. Gene expression profiling revealed that miR-155 deficiency in CD8+ T cells results in activation of type I Interferon (IFN) signaling and increased IFN sensitivity. This was confirmed by the increased expression of total and phosphorylated forms of STAT1 in miR-155 deficient CD8+ T cells. Importantly, miR-155 deficient CD8+ T cells are overtly susceptible to the anti-proliferative effect of IFN-01. Down-regulating individual miR-155 target genes did not restore miR-155 deficient CD8+ T cell responses, indicating that miR-155 may modestly regulate the expression of large sets of genes, resulting in profound effects on CD8+ T cell immunity. Our findings reveal a novel role for miR-155 in in vivo CD8+ T cell responses against intracellular pathogens.
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Details
- Title
- Role of microRNA-155 in CD8+ T cell responses
- Creators
- Donald T. Gracias
- Contributors
- Peter D. Katsikis (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xviii, 152 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991014970342504721