ORCID
https://orcid.org/0000-0001-8536-4628
Date of Award
8-25-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Inborn errors of immunity (IEIs) are disorders caused by monogenic variants that lead to immune deficiency and dysregulation. Although rare, IEIs have shaped our understanding of how single genes function in the immune systems of both humans and mice. The identification of loss-of-function (LOF) and gain-of-function (GOF) variants in the highly conserved signal transducer and activator of transcription (STAT) family molecules have led to discoveries involving how STAT signaling affects immune cell development, differentiation, and the induction and regulation of immune responses. Germline GOF variants in STAT3 cause early-onset multi-organ autoimmunity and immune dysregulation. Patients with STAT3 GOF syndrome have been treated successfully with inhibitors of upstream STAT3 signaling; however, the pleiotropic nature of STAT3 expression makes the identification of mechanisms that initiate disease difficult. Furthermore, tissue sampling limited to the peripheral blood of patients creates additional challenges in understanding how GOF variants affect cell types in specific environments. Our group recently generated and described a mouse model of STAT3 GOF that displays T cell dysregulation that increases with age. We hypothesized that T cell dysregulation in STAT3 GOF requires an inflammatory stimulus that would lead to autoimmune disease as seen in patients, and that this stimulus would activate tissue-specific inflammatory responses. In line with patient observations, we found that skin inflammation occurs spontaneously with age and is associated with increased local Th17 responses and neutrophil infiltration. A similar phenotype was elicited in younger mice with immune stimulation using the imiquimod (IMQ) model of skin inflammation, with increased IL-17A and IL-22 production by local Th17 cells that was cell-intrinsic. IMQ-induced skin inflammation was not dependent on CD8+ T cells or γδ T cells, and CD4+ T cells were sufficient to drive increased inflammation in STAT3 GOF mice. Single-cell analysis of T cells identified an increased CD4+ T clonal response with upregulated Il22 expression in expanded clones. IL-22 partially mediated the increased inflammation in STAT3 GOF. Concurrent treatment with IMQ and tofacitinib, a JAK inhibitor, resulted in decreased skin inflammation without affecting Th17 cytokine expression. In summary, this work suggests a role for Th17 in the development of autoimmunity in STAT3 GOF syndrome and presents a target for treatment that may not be affected by current therapies.
Language
English (en)
Chair and Committee
Megan Cooper
Recommended Citation
Toth, Kelsey Adele, "A Human STAT3 GOF Variant Alters T Cell Function to Drive Skin Inflammation" (2023). Arts & Sciences Electronic Theses and Dissertations. 3140.
https://openscholarship.wustl.edu/art_sci_etds/3140