γδ T Cells in Autoinflammatory Diseases

TL;DR

γδ T cells play a key role in autoinflammatory diseases by linking innate immune activation to tissue inflammation, suggesting new therapeutic strategies.

Contribution

This paper reviews evidence showing γδ T cells as central modulators in various autoinflammatory diseases, highlighting their altered functions and cytokine profiles.

Findings

γδ T cells display altered frequencies and activation states in diseases like familial Mediterranean fever and Behçet’s disease.

Transcriptomic analyses show γδ T cells accumulate at sites of sterile inflammation and exhibit functional specialization.

Skewed γδ T cell cytokine production, such as increased IL-17 and reduced IFNγ, amplifies inflammation in inflammasome-driven diseases.

Abstract

Autoinflammatory diseases are characterized by inappropriate activation of innate immunity resulting in excessive or persistent inflammation in the absence of infection. γδ T cells possess innate-like properties, including rapid responsiveness to stress-induced self-molecules, phosphoantigens, and inflammasome-derived cytokines, while retaining adaptive effector functions. Neutrophils and macrophages are well-established drivers of autoinflammatory disease, but increasing evidence implicates γδ T cells as key intermediaries by linking innate immune activation to tissue-specific inflammatory pathology. Here, we review evidence that in both monogenic and multifactorial autoinflammatory diseases—including, for example, familial Mediterranean fever, hyper-immunoglobulin (Ig) D syndrome, gout, Behçet’s disease, Still’s disease, atherosclerosis, and neurodegenerative disorders—γδ T cells display altered frequencies, activation states, cytokine polarization, and tissue recruitment. In inflammasome-driven diseases, skewing of γδ T cells toward interleukin (IL)-17 production has been observed, often accompanied by reduced interferon (IFN)γ secretion, thereby amplifying neutrophilic inflammation and tissue damage. In other diseases, e.g., Behcet’s disease, IFNγ and tumor necrosis factor (TNF)α producton predominate. Transcriptomic and tissue-based analyses support the accumulation and functional specialization of γδ T cells at sites of sterile inflammation. Collectively, these findings position γδ T cells as central amplifiers and modulators of inappropriate innate immune activation in the context of autoinflammatory diseases. Improved understanding of γδ T cell subset-specific regulation may inform novel therapeutic strategies targeting autoinflammatory diseases.

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