Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets

Cindy, S.; Wong, Natalie; Rao, Geetha; Nguyen, Akira; Avery, Danielle T.; Payne, Kathryn; Torpy, James R.; O’Young, Patrick; Deenick, Elissa K.; Bustamante, Jacinta; Puel, Anne; Okada, Satoshi; Kobayashi, Masao; Martı́nez-Barricarte, Rubén; Elliott, Michael R.; Kılıç, Sara Şebnem; Baghdadi, Jamila El; Minegishi, Yoshiyuki; Bousfiha, Aziz; Robertson, Nicholas; Hambleton, Sophie; Arkwright, Peter D.; French, Martyn A.; Blincoe, Annaliesse; Hsu, Peter; Campbell, Dianne; Stormon, Michael; Wong, Melanie; Adelstein, Stephen; Fulcher, David A.; Cook, Matthew C.; Stepensky, Polina; Boztuğ, Kaan; Beier, Rita; İkincioğulları, Aydan; Ziegler, John B.; Gray, Paul; Pïcard, Capucine; Boisson–Dupuis, Stéphanie; Phan, Tri Giang; Grimbacher, Bodo; Warnatz, Klaus; Holland, Steven M.; Uzel, Gülbû; Casanova, Jean‐Laurent; Tangye, Stuart G.

doi:10.1084/jem.20151467

Cited by 80 publications

(121 citation statements)

References 86 publications

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“…The T FH cells of both pt 1 and pt 2 exhibited high expression of the pro-T H 1 chemokine receptor CXCR3 and decreased expression of the pro-T H 17 chemokine receptor CCR6, in agreement with previous studies (Figure 3D). 37, 38 …”

Section: Resultsmentioning

confidence: 99%

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

Weinacht

Charbonnier

Alroqi

et al. 2017

Journal of Allergy and Clinical Immunology

144

105

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Background Gain of function (GOF) mutations in the human Signal Transducer and Activator of Transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity with impaired T helper (TH) 17 cell differentiation and exaggerated responsiveness to types I and II interferon. Allogeneic bone marrow transplantation has been attempted in severely affected patients but outcomes have been poor. Objective We sought to define the effect of increased STAT1 activity on T helper cell polarization and to investigate the therapeutic potential of ruxolitinib in treating autoimmunity secondary to STAT1 GOF mutations. Methods We used in vitro polarization assays as well as phenotypic and functional analysis of STAT1-mutated patient cells. Results We report on a child with a novel mutation in the linker domain of STAT1 who suffered from life-threatening autoimmune cytopenias and chronic mucocutaneous candidiasis. Naïve patient lymphocytes displayed increased TH1 and T follicular helper (TFH) cell as well as suppressed TH17 cell responses. The mutation augmented cytokine-induced STAT1 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase (JAK) 1/2 inhibitor ruxolitinib reduced hyper-responsiveness to types I and II interferon, normalized TH1 and TFH cell responses, improved TH17 differentiation, cured mucocutaneous candidiasis and maintained remission of immune mediated cytopenias. Conclusions Autoimmunity and infection due to STAT1 GOF mutations is caused by dysregulated T helper cell responses. JAK inhibitor therapy could represent an effective targeted treatment for long-term disease control in severely affected patients for whom hematopoietic stem cell transplantation is not available.

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Section: Resultsmentioning

confidence: 99%

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

Weinacht

Charbonnier

Alroqi

et al. 2017

Journal of Allergy and Clinical Immunology

144

105

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“…This is especially true for human Tfh, where IL-12 takes place of IL-6, and where mechanistic studies remain limited 27,45 . Approaches to understanding human Tfh responses, such as the recently performed in vitro screen of recombinant proteins in human Tfh differentiation and the evaluation of genotype and phenotype in human primary immunodeficiencies are of particular value to identifying which findings in mice can be potentially translated to humans 46,47 .…”

Section: Viral Infections and The T Cell Responsementioning

confidence: 99%

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

Vella

Herati

Wherry

2017

Trends in Molecular Medicine

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CD4+ T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4+ T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable Th1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure. However, recent data suggest that Th1 dysfunction is accompanied by a shift in the differentiation pathway of virus-specific CD4+ T cells, with enrichment for cells with a T follicular helper cell (Tfh) phenotype. A Tfh-like program during chronic infection has now been identified in virus-specific CD8+ T cells as well. In this review, we discuss what is known about CD4+ T cell differentiation in chronic viral infections, with a focus on the emergence of the Tfh program and the implications of this shift with respect to Tfh function and the host-pathogen interaction.

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“…клетки, которые экспрессируют факторы транс-крипции RORγt, T-bet, хемокиновые рецепторы CXCR3, CCR6 и продуцируют цитокины IFN-γ, IL-17, IL-22. Человеческие Th 1 -, Th 17 -, Th 1/17 -клетки играют важную роль в защите макроорганизма от различных патогенов [2,6,40].…”

Section: αβò-êëåòêè àäàïòèâíîé èììóííîé ñèñòåìûunclassified

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 8)

Абатуров¹,

Никулина²

2021

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У статті на підставі літературних джерел продемонстрована роль клітинних реакцій у розвитку імунної відповіді при пневмонії, викликаній Staphylococcus aureus. Описано механізми взаємодії Staphylococcus aureus з Т-клітинами адаптивної імунної системи, В-лімфоцитами. Подано порівняльну характеристику активації Т-клітин конвенціональним антигеном і суперантигеном бактерій Staphylococcus aureus, описані спадкові захворювання з порушеннями Тh17-асоційованого сигнального шляху, пов’язані з ризиком розвитку стафілококової інфекції. Продемонстровано основні механізми бактеріального кілингу імуноцитів.

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Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets

Abstract: Tangye and collaborators use a series of mutants to elucidate the pathways required to generate distinct subsets of human effector CD4+ T cells.

Cited by 80 publications

References 86 publications

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 8)

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