Impaired Purinergic Axis as a Novel Mechanism of CD8+ T Cell Dysregulation in STAT3 Gain-of-Function Syndrome Jose Stebhen Campos Duran

Format:

Book

Thesis/Dissertation

Author/Creator:

Campos Duran, Jose Stebhen, author.

Contributor:

University of Pennsylvania. Immunology., degree granting institution.

Language:

English

Subjects (All):

Immunology.

Cellular biology.

Genetics.

0982.

0379.

0369.

0769.

Local Subjects:

Immunology.

Cellular biology.

Genetics.

0982.

0379.

0369.

0769.

Physical Description:

1 electronic resource (202 pages)

Contained In:

Dissertations Abstracts International 86-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

Signal transduction downstream of activating and inhibitory stimuli controls CD8+ T cell biology, however these external inputs can become uncoupled from transcriptional regulation in Primary Immune Regulatory Disorders. Gain-of-function (GOF) variants in STAT3 amplify cytokine signaling and cause a complex disorder characterized by early-onset autoimmunity, lymphoproliferation, recurrent infections, and immune dysregulation. In both primary human and mouse models of STAT3 GOF, CD8+ T cells have been implicated as pathogenic drivers of autoimmunity, though the exact mechanisms remain poorly understood. Here, we investigated the molecular mechanisms by which STAT3 GOF variants drive this pathology. We first investigated how the CD8+ T cell compartment is dysregulated in patients with STAT3 GOF. We found that STAT3 GOF CD8+ T cells exist in an activated state both phenotypically and transcriptionally. Functional assessment revealed that naive CD8+ T cells in STAT3 GOF have an increased capacity for IFN-γ and TNF-α secretion. We explored immunoregulatory pathways that could be altered in these patients and found evidence of dysregulated purinergic signaling via high dimensional immune profiling, single-cell RNA sequencing, and functional assessment. Specifically, while CD39, which transforms ATP to AMP, was increased on CD8+ T cells from patients with STAT3 GOF, downstream purinergic family members, CD73 and the adenosine receptor, A2AR, were downregulated, impairing the potential to produce or sense inhibitory adenosine. Patients with STAT3 GOF can be clinically treated with JAK inhibitors and this partially normalized naive CD8+ T cell dysregulation, including aberrant cytokine production. The extent of normalization of cytokine secretion scaled with normalization of CD73 and A2AR. Finally, we investigated the role of STAT3 in modulating expression purinergic molecules through in vitro studies in human and mouse cells, mouse models of STAT3 GOF, and an overexpression system. Together, this body of work suggests that a dysregulated purinergic signaling axis plays a key role in CD8+ T cell dysregulation in STAT3 GOF, which may have implications for other rare monogenic immune disorders and more common inflammatory disorders with amplified STAT signaling

Notes:

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

Advisors: Henrickson, Sarah E. Committee members: Bailis, Will; Hunter, Christopher A.; Kambayashi, Taku; Cooper, Megan A.

Ph.D. University of Pennsylvania 2025

Local Notes:

School code: 0175

ISBN:

9798280759725

Access Restriction:

Restricted for use by site license