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

Nat Commun. 2019 Aug 28;10(1):3878. doi: 10.1038/s41467-019-11858-7.


T cell-mediated autoimmunity encompasses diverse immunopathological outcomes; however, the mechanisms underlying this diversity are largely unknown. Dysfunction of the tripartite linear ubiquitin chain assembly complex (LUBAC) is associated with distinct autonomous immune-related diseases. Cpdm mice lacking Sharpin, an accessory subunit of LUBAC, have innate immune cell-predominant dermatitis triggered by death of LUBAC-compromised keratinocytes. Here we show that specific gene ablation of Sharpin in mouse Treg causes phenotypes mimicking cpdm-like inflammation. Mechanistic analyses find that multiple types of programmed cell death triggered by TNF from tissue-oriented T cells initiate proinflammatory responses to implicate innate immune-mediated pathogenesis in this T cell-mediated inflammation. Moreover, additional disruption of the Hoip locus encoding the catalytic subunit of LUBAC converts cpdm-like dermatitis to T cell-predominant autoimmune lesions; however, innate immune-mediated pathogenesis still remains. These findings show that T cell-mediated killing and sequential autoinflammation are common and crucial for pathogenic diversity during T cell-mediated autoimmune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Autoimmunity
  • Dermatitis / immunology*
  • Dermatitis / pathology
  • Immunity, Innate
  • Inflammation / immunology
  • Inflammation / pathology
  • Keratinocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • T-Lymphocytes
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / metabolism


  • Nerve Tissue Proteins
  • Ubiquitin
  • sharpin
  • Ubiquitin-Protein Ligases