Modulation of autoimmune pathogenesis by T cell-triggered inflammatory cell death

Area of Science:

• Immunology
• Molecular Biology
• Dermatology

Background:

• T cell-mediated autoimmunity presents diverse outcomes, with underlying mechanisms poorly understood.
• Dysfunction of the tripartite linear ubiquitin chain assembly complex (LUBAC) links to specific immune-related diseases.
• Cpdm mice lacking Sharpin, a LUBAC subunit, develop dermatitis due to LUBAC-compromised keratinocyte death.

Purpose of the Study:

• Investigate the role of Sharpin in Treg cells in T cell-mediated inflammation.
• Elucidate the mechanisms driving pathogenic diversity in T cell-mediated autoimmune responses.
• Determine the contribution of programmed cell death and autoinflammation to autoimmune pathogenesis.

Main Methods:

• Generated mice with specific gene ablation of Sharpin in Treg cells.
• Analyzed inflammatory phenotypes and cell death pathways.
• Investigated the impact of additional LUBAC subunit disruption (Hoip locus).

Main Results:

• Specific ablation of Sharpin in mouse Treg cells induced cpdm-like inflammation.
• TNF-triggered programmed cell death by T cells initiated proinflammatory responses.
• Disruption of the Hoip locus in Sharpin-deficient mice shifted dermatitis to T cell-predominant autoimmune lesions, yet innate immunity remained involved.

Conclusions:

• T cell-mediated killing and subsequent autoinflammation are critical drivers of pathogenic diversity in T cell-mediated autoimmune diseases.
• LUBAC dysfunction contributes to distinct autoimmune pathologies through programmed cell death and inflammatory signaling.
• Innate immune mechanisms play a persistent role in T cell-mediated inflammatory diseases, even with genetic LUBAC alterations.