Dysfunctional KLRB1⁺CD8⁺ T-cell responses are generated in chronically inflamed systemic sclerosis skin

Area of Science:

• Immunology
• Dermatology
• Cell Biology

Background:

• Diffuse cutaneous systemic sclerosis (dcSSc) is characterized by chronic inflammation, vasculopathy, and extensive skin fibrosis, leading to significant patient morbidity.
• Current therapeutic strategies for dcSSc skin disease are limited, highlighting the need for a deeper understanding of its underlying immune mechanisms.

Purpose of the Study:

• To investigate the immune mechanisms of dcSSc skin disease by focusing on CD8+ T-cell responses within affected skin.
• To identify specific CD8+ T-cell subpopulations and their roles in the pathogenesis of dcSSc.

Main Methods:

• Single-cell transcriptomics and epigenomics were employed on patient skin samples to characterize skin-resident CD8+ T-cell subsets.
• Multicolor immunofluorescence microscopy validated molecular findings, and ex vivo skin explant assays assessed T-cell functionality.

Main Results:

• Two distinct CD8+ T-cell subpopulations were found to be expanded in SSc skin lesions compared to healthy controls.
• An effector-memory subset (CD8+KLRB1+IL7R+) was associated with early-stage tissue damage and fibrosis, while an exhausted subset (CD8+KLRG1+IL7R-) was linked to chronic inflammation in late-stage disease.
• Both identified subsets were also expanded in other benign dermatoses, suggesting a role in chronic skin inflammation.

Conclusions:

• This study reveals novel insights into CD8+ T-cell plasticity and identifies specific subpopulations driving the initiation and chronicity of inflammation in systemic sclerosis skin.
• The identified CD8+ T-cell subsets represent potential molecular targets for developing new therapeutic strategies for systemic sclerosis.