Abstract
The differentiation of naive CD8 T cells into effector cytotoxic T lymphocytes upon antigen stimulation is necessary for successful antiviral, and antitumor immune responses. Here, using a mouse model, we describe a dual role for the let-7 microRNAs in the regulation of CD8 T cell responses, where maintenance of the naive phenotype in CD8 T cells requires high levels of let-7 expression, while generation of cytotoxic T lymphocytes depends upon T cell receptor-mediated let-7 downregulation. Decrease of let-7 expression in activated T cells enhances clonal expansion and the acquisition of effector function through derepression of the let-7 targets, including Myc and Eomesodermin. Ultimately, we have identified a novel let-7-mediated mechanism, which acts as a molecular brake controlling the magnitude of CD8 T cell responses.
Highlights
CD8 T cells are responsible for the rapid clearance of virally infected, and cancerous cells in the organism
The initially very high expression of let-7 miRNAs in naive CD8 T cells was reduced by T cell receptor (TCR) signaling, and this downregulation was proportional to the strength and duration of TCR-stimulation, regardless of housekeeping RNA used (Figure 1A,B and Figure 1— figure supplement 1 and Figure 1—figure supplement 2A)
Our study has identified a critical role for the let-7 miRNAs in regulating the transition between naive and effector stages of CD8 T cells
Summary
CD8 T cells are responsible for the rapid clearance of virally infected, and cancerous cells in the organism. After antigen recognition, activated CD8 T cells undergo blastogenesis and rapid clonal expansion, which is followed by differentiation into effector cytotoxic T lymphocytes (CTLs), and memory T cells that are both capable of producing effector cytokines and killing target cells. These changes in T cells are accompanied by metabolic reprograming from oxidative phosphorylation to aerobic glycolysis that provides energy and larger amounts of the biomacromolecular intermediates needed to support growth (Ward and Thompson, 2012). The global regulation of these processes is not yet fully understood
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