Innate and Adaptive Immune Mechanisms of Pathogen-Specific T Helper 17 Cell Differentiation

dc.contributor.advisorNiederkorn, Jerry Y.en
dc.contributor.committeeMemberWakeland, Edward K.en
dc.contributor.committeeMemberPasare, Chandrashekharen
dc.contributor.committeeMemberPfeiffer, Julie K.en
dc.contributor.committeeMemberReese, Tiffany A.en
dc.contributor.committeeMemberFu, Yang-Xinen
dc.creatorGao, Yajingen
dc.creator.orcid0000-0002-8836-4452
dc.date.accessioned2022-01-03T22:15:28Z
dc.date.available2022-01-03T22:15:28Z
dc.date.created2019-12
dc.date.issued2019-12-09
dc.date.submittedDecember 2019
dc.date.updated2022-01-03T22:15:29Z
dc.descriptionPages 216-271 are misnumbered as pages 218-273.en
dc.description.abstractDendritic cells (DCs) are critical for the differentiation of pathogen-specific CD4 T cells. However, to what extent innate cues from DCs dictate transcriptional changes in T cells remains elusive. Here, we used DCs stimulated with distinct pathogens to prime CD4 T cells in vitro, and found that these T cells express unique transcriptional profiles dictated by the nature of the priming pathogen. More specifically, the transcriptome of in vitro pathogen-primed T helper 17 (Th17) cells resembled that of in vivo primed Th17 cells but was remarkably distinct from cytokine-polarized Th17 cells. We identified caspase-1 as one of the unique genes upregulated only in pathogen-primed Th17 cells and discovered a critical role for T-cell-intrinsic caspase-1, independent of its function in inflammasome, in optimal priming of Th17 responses. T cells lacking caspase-1 failed to induce colitis or confer protection to C. rodentium infection due to suboptimal Th17 cell differentiation in vivo. This study underlines the importance of DC-mediated priming in identifying novel regulators of T cell differentiation. DC sensing of fungal pathogens, certain commensal bacteria and extracellular enteric pathogens leads to the generation of Th17 response. However, the nature of specific innate signals that uniquely promote Th17 cells has not been fully understood. We find that sensing of C. rodentium and other enteric pathogens induces unfolded protein response (UPR) in DCs that is critical for Th17 differentiation. Mechanistically, activation of PERK-eIF2α-ATF4 arm of UPR in DCs selectively enhances the production of IL-6 and IL-23. Genetic ablation of PERK in DCs or pharmacological inhibition of eIF2α phosphorylation blunts the production of IL-23 and IL-6, leading to impairment of Th17/22 differentiation and defective protection against enteropathogenic infection. Additionally, forced induction of UPR led to Th17 cell differentiation by non-Th17-inducing pathogens. We propose that the integration of PRR signaling with other sensors of disturbed cellular homeostasis, such as pathogen-induced stress, allows the innate immune system to induce tailored adaptive immune responses.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1290684160
dc.identifier.urihttps://hdl.handle.net/2152.5/9650
dc.language.isoenen
dc.subjectCaspase 1en
dc.subjectCell Differentiationen
dc.subjectTh17 Cellsen
dc.subjectTranscription, Geneticen
dc.titleInnate and Adaptive Immune Mechanisms of Pathogen-Specific T Helper 17 Cell Differentiationen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineImmunologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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