ORCID
http://orcid.org/0000-0002-2336-956X
Date of Award
Spring 5-15-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
T cells are potent immune responders and cytokine producers. Appropriate regulation of T cell-derived cytokines is needed to allow enough production to coordinate immune responses but restrict excessive production to limit tissue damage. Herein, we explore post-transcriptional and transcriptional control of T cell cytokine production in multiple contexts. We find that during homeostasis, CD4+ and CD8+ T cells require the collective functions of the ZFP36 family of RNA-binding proteins (ZFP36, ZFP36L1, and ZFP36L2) to negatively cytokine production. Triple deletion of ZFP36 family members exclusively in T cells results in a spontaneous and lethal autoinflammatory syndrome not present when deleting any combination of two ZFP36 family members, highlighting their functional redundancy. The ZFP36 family members collectively promote the normal degradation of cytokine mRNAs and prevent cytokine protein production.
In contrast to their functional redundancy during homeostasis, we find that ZFP36L1 and ZFP36L2 are uniquely required to support CD4+ T cell encephalitogenicity during experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. T cell-specific deletion of ZFP36L1 and ZFP36L2 results in diminished antigen-specific priming of CD4+ T cell responses, potentially from impaired fitness of antigen-specific T cells. Our studies reveal that, depending on the immunological context, there is functional redundancy within the ZFP36 family members that is crucial for regulating different types of T cell responses.
We also examine the role of transcription factor Bhlhe40 in TH17 cells during EAE. We find that deletion of Bhlhe40 in IL-17A-producing cells (Il17a-Cre) results in clinical protection comparable to deletion in all T cells (Cd4-Cre). Il17a-Cre Bhlhe40fl/fl mice have fewer cytokine producing CD4+ T cells in their central nervous system at the peak of disease during EAE, resulting in fewer and less activated infiltrating myeloid cells. We use single cell RNA-sequencing to further characterize changes in the infiltrating myeloid cell population when Bhlhe40 is absent in IL-17A-producing cells.
Language
English (en)
Chair and Committee
Brian T. Edelson
Committee Members
Maxim Artyomov, Megan Cooper, Deborah Lenschow, Gregory Wu,
Recommended Citation
Cook, Melissa Erin, "ZFP36 Family-Mediated Post-Transcriptional and Bhlhe40-Mediated Transcriptional Regulation of T Cell Responses" (2023). Arts & Sciences Electronic Theses and Dissertations. 2846.
https://openscholarship.wustl.edu/art_sci_etds/2846