Spatial Orchestration of Skin Fibrosis by a CD8+ T cell- Myofibroblast Axis

Area of Science:

• Immunology
• Dermatology
• Fibrosis Research

Background:

• Fibrosing skin diseases present diverse clinical and histopathologic features.
• Previous research on immune drivers of fibrosis in systemic sclerosis (SSc) yielded mixed results.
• Morphea and eosinophilic fasciitis (EF) are characterized by acute inflammatory skin fibrosis.

Purpose of the Study:

• To investigate the immune drivers and fibroblast populations in inflammatory skin fibrosis.
• To identify the spatial localization of pro-fibrotic fibroblast subsets in morphea and EF.
• To explore shared mechanisms of fibrosis across different skin fibrotic conditions.

Main Methods:

• Multimodal single-nucleus and spatial transcriptomics were employed.
• Analysis focused on fibrotic skin tissues from morphea and eosinophilic fasciitis.
• Investigated CD8+ T cell enrichment and their interaction with fibroblasts.
• Utilized mouse models for mechanistic studies (bleomycin-induced fibrosis).

Main Results:

• Effector CD8+ T cells are highly enriched in fibrotic skin, particularly near inflammatory domains.
• These domains show loss of homeostatic fibroblasts and gain of ADAM12-expressing inflammatory fibroblasts and myofibroblasts.
• CD8+ T cells co-localize with these activated fibroblasts.
• Similar patterns were observed in systemic sclerosis (SSc) datasets.
• Ablation of CD8+ T cells or fibroblast IFN-γ signaling ameliorated fibrosis in mice.

Conclusions:

• CD8+ T cell-driven fibrogenesis is a key mechanism in fibrosing skin diseases.
• Shared mechanisms of fibrosis exist across different skin fibrotic conditions.
• Targeting CD8+ T cells presents a potential therapeutic strategy for autoimmune fibrosis.