JCI Insight - Impaired regulation by purinergic signaling axis contributes to CD8+ T cell dysregulation in STAT3 gain of function

Impaired regulation by purinergic signaling axis contributes to CD8⁺ T cell dysregulation in STAT3 gain of function

Jose S. Campos Duran, Montana S. Knight, Samir U. Sayed, Megan C. Dalalo, Andrea A. Mauracher, Peyton Conrey, Aaron B. Schultz, Ceire A. Hay, Robert B. Lindell, Ilona Neale, Kyle Yeakle, Eric D. Abrams, Erica G. Schmitt, Martin A. Thelin, Christian A. Howard, Sara Bluestein, Christine M. Seroogy, Tamara C. Pozos, Akaluck Thatayatikom, Ingrid S. Lundgren, Amelie Gauthier, Scott W. Canna, Helen C. Su, Michael D. Keller, Ottavia M. Delmonte, Lisa R. Forbes Satter, Steven M. Holland, Jenna R.E. Bergerson, Jennifer W. Leiding, Neil Romberg, Will Bailis, Christopher A. Hunter, Alexandra F. Freeman, Alejandro V. Villarino, Mark S. Anderson, Megan A. Cooper, Tiphanie P. Vogel, Sarah E. Henrickson

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Research Article Immunology Metabolism

Impaired regulation by purinergic signaling axis contributes to CD8⁺ T cell dysregulation in STAT3 gain of function

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Abstract

Gain-of-function (GOF) variants in STAT3 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 found that in patients with STAT3 GOF, CD8+ T cells exist in an activated state. Functional assessment revealed that naive CD8+ T cells have an increased capacity for IFN-γ and TNF-α production, with type I and type II IFN transcriptional signatures. Evaluation of immunoregulatory pathways revealed dysregulation of the purinergic signaling axis in CD8+ T cells: CD39 was increased, whereas downstream purinergic family members, CD73 and the adenosine receptor A2AR, were downregulated, impairing the potential to produce or sense immunosuppressive adenosine. Evaluation of the impact of precision therapy, in the form of JAK inhibition, at a cellular and functional level revealed partial normalization of CD8+ T cell dysregulation in patients, including aberrant cytokine production. Our study suggests that a dysregulated purinergic signaling axis plays a key role in CD8+ T cell dysregulation in STAT3 GOF and may have implications for other rare monogenic immune disorders and common inflammatory disorders.

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Figure 1

Patients with STAT3 GOF demonstrate a hyperactivated CD8⁺ T cell phenotype and transcriptional profile.

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(A) STAT3 protein domains with GOF variants indicated. (B) Frequencies of immune cell lineages in 8 untreated patients with STAT3 GOF and 21 age-matched healthy controls. (C) Frequencies of CD3⁺αβ⁺ T cell subsets after exclusion of NKT (CD3⁺CD56⁺), CD3⁺TCRγδ⁺, and MAIT (CD3⁺CD26⁺CD161⁺) cells; quantification of CD4/CD8 ratio. (D) Differentiation status of CD8⁺ T cells: naive, CD45RA⁺CD27⁺; central memory (CM), CD45RA^–CD27⁺; effector memory (EM), CD45RA^–CD27^–; EM reexpressing CD45RA (EMRA), CD45RA⁺CD27^–. (E) Activation and effector molecule expression on CD8⁺ T cells. (F) scRNA-Seq uniform manifold approximation and projection (UMAP) and cluster marker expression/annotation and (G) cluster proportion of sorted CD8⁺ T cells from 7 patients with STAT3 GOF and 5 age-matched healthy controls. (H) GSEA of pathways enriched in conventional CD8⁺ T cells. (I) Shannon Diversity Index and (J) proportion of expanded clones in patients with STAT3 GOF compared with healthy controls. (K) Visualization of TCR clonotypes overlaid on UMAPs and proportion of expanded TCR clones by cluster. For B–E: data are pooled from 3 independent experiments. Data represent mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001 by Mann-Whitney test. For G: *P ≤ 0.05, **P ≤ 0.01, ****P ≤ 0.0001 by propeller (2-tailed moderated t test). Not listed or ns was not statistically significant. Figure 1A was created in BioRender (https://BioRender.com/4pf5knc).

Impaired regulation by purinergic signaling axis contributes to CD8+ T cell dysregulation in STAT3 gain of function

Impaired regulation by purinergic signaling axis contributes to CD8+ T cell dysregulation in STAT3 gain of function

Abstract

Authors

Figure 1

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Impaired regulation by purinergic signaling axis contributes to CD8⁺ T cell dysregulation in STAT3 gain of function

Impaired regulation by purinergic signaling axis contributes to CD8⁺ T cell dysregulation in STAT3 gain of function