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Author ORCID Identifier
https://orcid.org/0000-0001-6086-0406
AccessType
Open Access Dissertation
Document Type
dissertation
Degree Name
Doctor of Philosophy (PhD)
Degree Program
Molecular and Cellular Biology
Year Degree Awarded
2020
Month Degree Awarded
May
First Advisor
Leonid Pobezinsky
Subject Categories
Immunity
Abstract
CD4+ and CD8+ T cells are lymphocytes of the adaptive immune system that play essential roles in immunity. Both T cell subsets recognize their cognate antigen through the T cell receptor (TCR), which induces the proliferation and differentiation of these antigen-specific cells into effector T cells. CD4+ T cells have the potential to differentiate into one of multiple lineages of helper T (Th) cells and participate indirectly in antigen clearance by orchestrating the function of other cells. CD8+ T cells differentiate into cytotoxic T lymphocytes (CTL), which directly contributes to the resolution of an infection by killing cancerous or virally-infected cells. Upon antigen clearance, most effector T cells die, but some survive and generate long-lived memory T cells that will respond faster and more efficiently to subsequent encounters with the same antigen. When antigen fails to be cleared, such as in chronic infections and cancer, effector T cells are diverted into a hyporesponsive state, exhaustion, characterized by the upregulation of co-inhibitory receptors that transmits inhibitory signals resulting in the loss of effector function and memory potential. Moreover, when T cell differentiation is dysregulated, T cell responses become aberrant, causing autoimmune diseases. Therefore, understanding the molecular mechanisms controlling T cell responses is important to develop innovative treatments that can enhance T cell activity during infections and cancer, and dampen the generation of disease-causing T cells in autoimmunity. We have uncovered a novel post-transcriptional mechanism regulating T cell differentiation. Particularly, we showed that the let-7 family of miRNAs is highly expressed in naive T cells, but gets dramatically downregulated upon antigen encounter, proportionally to both the strength and duration of TCR stimulation. Specifically, let-7 downregulation was required for the differentiation of pathogenic Th17 cells in experimental autoimmune encephalomyelitis (EAE), a mouse model of the autoimmune disease multiple sclerosis (MS). In CD8+ T cells, although let-7 inhibits CTL differentiation in vitro, let-7 was demonstrated both in silico and in vivo to promote memory CD8+ T cell formation, while repressing the differentiation of terminal effectors, which are susceptible to exhaustion. Thus, let-7 constitutes a promising tool for the therapeutic manipulation of T cell responses.
DOI
https://doi.org/10.7275/z0n5-td13
Recommended Citation
Angelou, Constance C., "Defining the let-7 microRNA-mediated molecular mechanisms regulating T cell differentiation" (2020). Doctoral Dissertations. 1901.
https://doi.org/10.7275/z0n5-td13
https://scholarworks.umass.edu/dissertations_2/1901
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License