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dc.contributor.advisorSlansky, Jill
dc.contributor.authorFernandez, Zoila Isabel
dc.contributor.committeememberClambey, Eric
dc.contributor.committeememberHuang, Hua
dc.contributor.committeememberReinhardt, Lee
dc.contributor.committeememberTorres, Raul
dc.date.accessioned2020-06-29T10:03:06Z
dc.date.available2022-06-22T10:03:06Z
dc.date.submitted2020
dc.descriptionIncludes bibliographical references.
dc.descriptionSpring
dc.description.abstractDelivery of recombinant IL-2 and IL-15 and the targeting of their receptors has emerged as a promising intervention strategy for treatment of autoimmunity, chronic infectious diseases and cancer. Therefore, a better understanding of IL-2/IL-15 biology is necessary, especially in respect to signal transduction. Even though IL-15 and IL-2 have distinct immunological functions, they both signal through receptor subunits, IL-2Rβ and γc. While work has shown that cell type-specific differences in IL-2Rβ abundance have a key role in tuning tolerogenic and immunogenic responses, the role of differential IL-2Rβ receptor expression and organization on IL-2/IL-15 signaling pathways remains undefined. Here, we explore the fine-tuning mechanisms of IL-2Rβ signaling by characterizing a human IL-2Rβ partial defect and the role of IL-2Rβ organization in mouse CD8+ T cells. The work presented in this thesis shows how a novel homozygous mutation in human IL2RB results in decreased IL-2Rβ protein expression and dysregulated IL-2/IL-15 signaling. This hypomorphic mutation leads to decreased regulatory T cells (Tregs) and an abnormal and immature Natural Killer (NK) cell compartment, with affected individuals presenting with autoimmunity and susceptibility to CMV. This part describes the immunological and signaling consequences of a hypomorphic IL-2Rβ defect. The second part of this thesis explores the modulation of IL-15 signaling by IL-2Rβ organization in memory relative to naïve CD8+ T cells. We demonstrate that memory CD8+ T cells contain large IL-2Rβ homomeric clusters compared to their naïve counterparts. With IL-15 stimulation, we show that IL-2Rβ clusters localize to lipid microdomains in both subsets. However, while lipid disruption inhibits naïve and memory signaling and impedes IL-2Rβ association with lipid microdomains in memory cells, memory cells transduce sufficient signal to survive in contrast to naïve CD8+ T cells. These results suggest that subset-specific mechanisms of IL-2Rβ organization might play a role in the modulation of IL-15 signaling. Overall, our data provides critical insights into manipulating the IL-2/IL-15 pathway via IL-2Rβ expression and organization.
dc.format.mediumborn digital
dc.format.mediumdoctoral dissertations
dc.identifierFernandez_ucdenveramc_1639D_10729.pdf
dc.identifier.urihttps://hdl.handle.net/10968/5499
dc.languageEnglish
dc.publisherUniversity of Colorado at Denver, Anschutz Medical Campus. Health Sciences Library
dc.relation.ispartof2017 to Current
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 06/22/2022
dc.subject.meshReceptors, Interleukin-2
dc.subject.meshMemory
dc.subject.meshPrimary Immunodeficiency Diseases
dc.subject.meshLipids
dc.subject.meshInterleukin-2 Receptor beta Subunit
dc.subject.meshKiller Cells, Natural
dc.titleVariable IL-2Rβ expression and organization in signaling and disease
dc.typeText
dcterms.embargo.expires2022-06-22
thesis.degree.disciplineImmunology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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