Altered Purinergic Signaling and CD8+ T Cell Dysregulation in STAT3 GOF Syndrome

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Signal transduction regulates CD8+ T cell biology, but can be disrupted in Primary Immune Regulatory Disorders (PIRDs).
• Gain-of-function (GOF) variants in STAT3 lead to amplified cytokine signaling, causing severe PIRD with autoimmunity and immune dysregulation.
• CD8+ T cells are implicated as drivers of autoimmunity in STAT3 GOF PIRD, but the underlying mechanisms are unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which STAT3 GOF variants induce CD8+ T cell-driven autoimmunity.
• To investigate the role of purinergic signaling in CD8+ T cell dysfunction associated with STAT3 GOF.

Main Methods:

• High-dimensional immune profiling
• Single-cell RNA sequencing
• Functional assessment of CD8+ T cells
• Analysis of purinergic signaling pathway members (CD39, CD73, A2AR)

Main Results:

• Naive CD8+ T cells from STAT3 GOF patients exhibit increased IFN-γ and TNF-α secretion.
• STAT3 GOF is associated with dysregulated purinergic signaling: increased CD39 but decreased CD73 and A2AR expression on CD8+ T cells.
• JAK inhibitor treatment partially normalized CD8+ T cell function and purinergic signaling in STAT3 GOF patients.

Conclusions:

• A dysregulated purinergic signaling axis, characterized by impaired adenosine production and sensing, contributes to CD8+ T cell dysfunction in STAT3 GOF.
• Targeting the JAK-STAT pathway with inhibitors shows potential for treating CD8+ T cell dysregulation in STAT3 GOF.
• These findings suggest purinergic signaling dysregulation may be relevant in other inflammatory conditions with amplified STAT signaling.