A feedback control for restraining autoimmune γδ T cells: reprogramming into ILC1s

Area of Science:

• Immunology
• Autoimmunity
• Cancer Immunotherapy

Background:

• Gamma delta (γδ) T cells show promise in cancer immunotherapy but their role in autoimmunity is unclear.
• Innate-like Vγ1.1⁺Vδ6.3⁺ T cells are implicated in autoimmune pathology.

Purpose of the Study:

• To investigate a feedback mechanism involving γδ T cells that restrains autoimmune pathology.
• To define a novel innate lymphoid cell type 1 (ILC1) subset and its developmental dependence.

Main Methods:

• Analysis of T cell receptor (TCR) signaling pathways.
• Genetic ablation of Id3 in T cells.
• Characterization of ILC1 subsets and their development.
• Comparison of murine findings with human Sjögren's disease patient samples.

Main Results:

• A new ILC1 subset dependent on the T cell receptor (Tcrd) locus was identified.
• TCR signaling induces Id3, suppressing Vδ6.3 expression and reprogramming Vγ1.1⁺Vδ6.3⁺ T cells into ILC1-like cells.
• Id3 deficiency led to severe autoimmunity, including autoantibody production and T follicular helper cell differentiation, mimicking Sjögren's disease.
• Human Sjögren's disease patients showed increased γδ T cells in salivary glands.

Conclusions:

• A TCR-Id3-dependent reprogramming pathway limits the pathogenic potential of γδ T cells.
• This mechanism restrains autoimmune pathology and offers potential therapeutic targets for autoimmune diseases like Sjögren's.
• Innate-like γδ T cells can differentiate into ILC1-like cells, highlighting immune cell plasticity.