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Impaired Purinergic Axis as a Novel Mechanism of CD8+ T Cell Dysregulation in STAT3 Gain-of-Function Syndrome
Impaired Purinergic Axis as a Novel Mechanism of CD8+ T Cell Dysregulation in STAT3 Gain-of-Function Syndrome
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103156
- ISBN
- 9798280759725
- DDC
- 616.079
- 서명/저자
- Impaired Purinergic Axis as a Novel Mechanism of CD8+ T Cell Dysregulation in STAT3 Gain-of-Function Syndrome
- 발행사항
- [Sl] : University of Pennsylvania, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 202 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 주기사항
- Advisor: Henrickson, Sarah E.
- 학위논문주기
- Thesis (Ph.D.)--University of Pennsylvania, 2025.
- 초록/해제
- 요약Signal 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.
- 일반주제명
- Immunology
- 일반주제명
- Cellular biology
- 일반주제명
- Genetics
- 키워드
- Gain-of-function
- 키워드
- Autoimmunity
- 키워드
- Patients
- 기타저자
- University of Pennsylvania Immunology
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798280759725
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616.079
■1001 ▼aCampos Duran, Jose Stebhen.
■24510▼aImpaired Purinergic Axis as a Novel Mechanism of CD8+ T Cell Dysregulation in STAT3 Gain-of-Function Syndrome
■260 ▼a[Sl]▼bUniversity of Pennsylvania▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a202 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aAdvisor: Henrickson, Sarah E.
■5021 ▼aThesis (Ph.D.)--University of Pennsylvania, 2025.
■520 ▼aSignal 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.
■590 ▼aSchool code: 0175.
■650 4▼aImmunology
■650 4▼aCellular biology
■650 4▼aGenetics
■653 ▼aGain-of-function
■653 ▼aCD8+ T cell biology
■653 ▼aAutoimmunity
■653 ▼aImmune dysregulation
■653 ▼aPatients
■690 ▼a0982
■690 ▼a0379
■690 ▼a0369
■690 ▼a0769
■71020▼aUniversity of Pennsylvania▼bImmunology.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■790 ▼a0175
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357252▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
