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

View: Text | PDF

Research Article Immunology Metabolism

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

Text
PDF

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.

Authors

Figure 4

Impact of therapy (JAKi with or without αIL-6R) on aberrant CD8⁺ T cell phenotype and function.

Options: View larger image (or click on image) Download as PowerPoint

(A) Study schematic comparing samples from patients with STAT3 GOF not receiving immune modulatory therapy (red) to samples from patients with STAT3 GOF receiving immune modulatory therapy (blue). (B) Proportion of CD8⁺, CD4⁺, double-negative (DN), and double-positive (DP) cells within CD3⁺ cells in untreated (n = 14) and treated (n = 9) patients with STAT3 GOF. Impact of treatment on (C) CD8⁺ T cell differentiation and (D) activation markers in untreated (n = 7–14) and treated (n = 6–9) patients with STAT3 GOF. Impact of treatment on (E) IFN-γ cytokine production (n = 14 untreated STAT3 GOF patients; n = 8 treated STAT3 GOF patients) and (F) TNF-α cytokine production by CD8⁺ T cell subsets (n = 11 untreated STAT3 GOF patients; n = 6 treated STAT3 GOF patients). IFN-γ and TNF-α values from untreated STAT3 GOF patients used for Figure 5, E and F, were used in Figure 2D and Figure 2C, respectively. Blue square represents patient treated with rapamycin, rather than JAKi (blue circles). Data are pooled from 3 or more independent experiments for B and C and from 2–3 experiments for D–F. Data represent mean ± SEM. *P ≤ 0.05, **P ≤ 0.01 by Mann-Whitney test. Solid dashed line represents the average of 30-plus healthy controls. Figure 4A was created in BioRender (https://BioRender.com/4ut4e0o).

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 4

Sign up for email alerts

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