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Author ORCID Identifier

https://orcid.org/0000-0001-9799-8353

AccessType

Open Access Dissertation

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Molecular and Cellular Biology

Year Degree Awarded

2019

Month Degree Awarded

May

First Advisor

Leonid Pobezinsky

Subject Categories

Immunity

Abstract

CD8 T cells are the cytotoxic effectors of the adaptive immune response, clearing virally infected and cancerous cells within the host. CD8 T cells acquire their cytotoxic function by differentiating into cytotoxic T lymphocytes (CTLs). Once the CTLs have cleared the antigen, the majority of responding cells will die during contraction; however, a small population of the antigen-specific responders will remain, differentiating into long-lived memory cells that provide potent protection to the host upon re-encounter with the antigen. These differentiation programs often become disturbed in cases of chronic infection and cancer. Instead, CD8 T cells are subverted into the so-called exhausted state, in which cells become functionally inert. As such, the ability to program the differentiation of CD8 T cells into a particular fate is an important therapeutic strategy. We have identified a global post-transcriptional mechanism that determines the fate of differentiating CD8 T cells. Specifically, we have found that the let-7 family of miRNAs is abundantly expressed in naïve CD8 T cells, and that this expression is downregulated upon T cell receptor signaling. The expression of let-7 in naïve CD8 T cells was demonstrated to be necessary and sufficient to maintain the quiescent state of naïve cells. Accordingly, the down-regulation of let-7 is necessary for the differentiation of naïve CD8 T cells into cytotoxic T lymphocytes in vitro. However, let-7 expression had paradoxical effects on CD8 T cell function in vitro and in vivo. Specifically, loss of let-7 expression drives the differentiation of terminal effector CD8 T cells, which in immunosuppressive environments in vivo, are diverted into the exhausted state. Accordingly, maintaining let-7 expression restrained terminal effector differentiation, and programmed CD8 T cells to differentiate into highly protective memory cells. These findings may have important implications for the improvement of current immunotherapies targeting CD8 T cell fate.

DOI

https://doi.org/10.7275/14175413

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