Abstract
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.
Highlights
T cell-mediated autoimmunity encompasses diverse immunopathological outcomes; the mechanisms underlying this diversity are largely unknown
Upon TNFα signaling, the ligase activity of linear ubiquitin chain assembly complex (LUBAC) is requisite for protection against two types of programmed cell death, apoptosis and necroptosis; the latter is induced by generation of cytosolic death-inducible complex II comprising receptor-interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, FAS-associated death domain protein (FADD), cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein, and Caspase-89,10
Sharpin-deficient skin transplanted onto nude mice develops autonomous inflammatory responses that clearly indicate that keratinocytes showing hypomorphic LUBAC expression are susceptible to autonomous cell death mediated by FADD-caspase-8-dependent apoptosis and RIPK1-RIPK3-mixed-lineage kinase domain-like protein (MLKL)-dependent necroptosis, resulting in autoinflammation even under steady-state conditions[19]
Summary
T cell-mediated autoimmunity encompasses diverse immunopathological outcomes; the mechanisms underlying this diversity are largely unknown. Additional disruption of the Hoip locus encoding the catalytic subunit of LUBAC converts cpdm-like dermatitis to T cell-predominant autoimmune lesions; innate immune-mediated pathogenesis still remains. Sharpin-deficient skin transplanted onto nude mice develops autonomous inflammatory responses that clearly indicate that keratinocytes showing hypomorphic LUBAC expression are susceptible to autonomous cell death mediated by FADD-caspase-8-dependent apoptosis and RIPK1-RIPK3-mixed-lineage kinase domain-like protein (MLKL)-dependent necroptosis, resulting in autoinflammation even under steady-state conditions[19]. Adaptive transfer of Sharpin-sufficient Treg into neonatal cpdm mice alleviates inflammatory responses in various tissues, but does not improve dermatitis[20,21] These reports imply that cpdm mice suffer from both autoimmune and autoinflammatory diseases, they exhibit predominantly innate immune-mediated inflammation. We examine the possibility that T cell-induced inflammation elicits an apparently innate immune-mediated pathogenesis, as observed in cpdm disease
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