A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice
Primary immune regulatory disorders (PIRD) represent a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease, including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 re...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-11-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.162695 |
| _version_ | 1797634390677782528 |
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| author | Erica G. Schmitt Kelsey A. Toth Samuel I. Risma Ana Kolicheski Nermina Saucier Rafael J. Feliciano Berríos Zev J. Greenberg Jennifer W. Leiding Jack J. Bleesing Akaluck Thatayatikom Laura G. Schuettpelz John R. Edwards Tiphanie P. Vogel Megan A. Cooper |
| author_facet | Erica G. Schmitt Kelsey A. Toth Samuel I. Risma Ana Kolicheski Nermina Saucier Rafael J. Feliciano Berríos Zev J. Greenberg Jennifer W. Leiding Jack J. Bleesing Akaluck Thatayatikom Laura G. Schuettpelz John R. Edwards Tiphanie P. Vogel Megan A. Cooper |
| author_sort | Erica G. Schmitt |
| collection | DOAJ |
| description | Primary immune regulatory disorders (PIRD) represent a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease, including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad clinical spectrum. Studies in patients have documented a decreased frequency of FOXP3+ Tregs and an increased frequency of Th17 cells in some patients with active disease. However, the mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown, and treatment is challenging. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation, and CD4+ Th1 cell skewing. Surprisingly, Treg numbers, phenotype, and function remained largely intact; however, mice had a selective deficiency in the generation of iTregs. In parallel, we performed single-cell RNA-Seq on T cells from STAT3 GOF patients. We demonstrate only minor changes in the Treg transcriptional signature and an expanded, effector CD8+ T cell population. Together, these findings suggest that Tregs are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD. |
| first_indexed | 2024-03-11T12:07:02Z |
| format | Article |
| id | doaj.art-d12a4668e30f4d379c2f85598786cc63 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:07:02Z |
| publishDate | 2022-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-d12a4668e30f4d379c2f85598786cc632023-11-07T16:24:47ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-11-01721A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in miceErica G. SchmittKelsey A. TothSamuel I. RismaAna KolicheskiNermina SaucierRafael J. Feliciano BerríosZev J. GreenbergJennifer W. LeidingJack J. BleesingAkaluck ThatayatikomLaura G. SchuettpelzJohn R. EdwardsTiphanie P. VogelMegan A. CooperPrimary immune regulatory disorders (PIRD) represent a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease, including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad clinical spectrum. Studies in patients have documented a decreased frequency of FOXP3+ Tregs and an increased frequency of Th17 cells in some patients with active disease. However, the mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown, and treatment is challenging. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation, and CD4+ Th1 cell skewing. Surprisingly, Treg numbers, phenotype, and function remained largely intact; however, mice had a selective deficiency in the generation of iTregs. In parallel, we performed single-cell RNA-Seq on T cells from STAT3 GOF patients. We demonstrate only minor changes in the Treg transcriptional signature and an expanded, effector CD8+ T cell population. Together, these findings suggest that Tregs are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.https://doi.org/10.1172/jci.insight.162695Immunology |
| spellingShingle | Erica G. Schmitt Kelsey A. Toth Samuel I. Risma Ana Kolicheski Nermina Saucier Rafael J. Feliciano Berríos Zev J. Greenberg Jennifer W. Leiding Jack J. Bleesing Akaluck Thatayatikom Laura G. Schuettpelz John R. Edwards Tiphanie P. Vogel Megan A. Cooper A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice JCI Insight Immunology |
| title | A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice |
| title_full | A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice |
| title_fullStr | A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice |
| title_full_unstemmed | A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice |
| title_short | A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice |
| title_sort | human stat3 gain of function variant confers t cell dysregulation without predominant treg dysfunction in mice |
| topic | Immunology |
| url | https://doi.org/10.1172/jci.insight.162695 |
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