A Defect in Thymic Tolerance Causes T Cell–Mediated Autoimmunity in a Murine Model of COPA Syndrome

Abstract

COPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the coatomer protein complex subunit a (COPA) gene. Patients with COPA syndrome develop arthritis and lung disease that presents as pulmonary hemorrhage or interstitial lung disease (ILD). Immunosuppressive medications can stabilize the disease, but many patients develop progressive pulmonary fibrosis, which requires life-saving measures, such as lung transplantation. Because very little is understood about the pathogenesis of COPA syndrome, it has been difficult to devise effective treatments for patients. To date, it remains unknown which cell types are critical for mediating the disease as well as the mechanisms that lead to autoimmunity. To explore these issues, we generated a Copa E241K/+ germline knock-in mouse bearing one of the same Copa missense mutations in patients. Mutant mice spontaneously developed ILD that mirrors lung pathology in patients, as well as elevations of activated cytokine-secreting T cells. In this study, we show that mutant Copa in epithelial cells of the thymus impairs the thymic selection of T cells and results in both an increase in autoreactive T cells and decrease in regulatory T cells in peripheral tissues. We demonstrate that T cells from Copa E241K/+ mice are pathogenic and cause ILD through adoptive transfer experiments. In conclusion, to our knowledge, we establish a new mouse model of COPA syndrome to identify a previously unknown function for Copa in thymocyte selection and demonstrate that a defect in central tolerance is a putative mechanism by which COPA mutations lead to autoimmunity in patients.

Homeostatic regulation of STING by retrograde membrane traffic to the ER

“…In this study, we demonstrate the homeostatic regulation of STING at the resting state by the retrograde membrane traffic. Intriguingly, this finding is corroborated in a recently described mouse model of COPA syndrome ( Copa E241K/+ mice) 27 : Copa E241K/+ mice exhibit spontaneous activation of STING with upregulation of type I interferon signaling and systemic inflammation, all of which is abrogated in STING-deficient animals 28 . However, given the multiple cargo proteins transported by COP-I vesicles, other effects of α-COP loss-of-function may also contribute to the COPA syndrome-specific symptoms, which are not manifested in SAVI in which STING is constitutively active because of the STING mutations.…”

Homeostatic regulation of STING by Golgi-to-ER membrane traffic

“…In this study, we demonstrate the homeostatic regulation of STING at the resting state by Golgi-to-ER membrane traffic. Intriguingly, this finding is corroborated in a recently described mouse model of COPA syndrome (Copa E241K/+ mice) 24 : Copa E241K/+ mice exhibit spontaneous activation of STING with upregulation of type I interferon signalling and systemic inflammation, all of which is abrogated in STING-deficient animals 25 . Our results that the inflammatory response in the presence of COPA variants can be effectively suppressed by STING palmitoylation inhibitors may provide a new treatment approach for COPA syndrome patients 25 .…”

A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome

“…We next turned to a mouse model of COPA syndrome to understand how mutant COPA-mediated STING activation causes immune dysregulation in vivo. We previously reported that Copa E241K/+ mice, which express one of the same disease-causative mutations as patients, spontaneously develop activated cytokine-secreting T cells and T cell–mediated lung disease ( Deng et al, 2020 ). Through bone marrow chimera and thymic transplant experiments, we showed that mutant COPA within thymic epithelial cells perturbs thymocyte development and leads to a defect in immune tolerance.…”

“…Copa E241K knock-in mice were generated in our laboratory ( Deng et al, 2020 ). C57BL/6J- Sting1 gt /J ( Sting gt/gt ) mice were purchased from The Jackson Laboratory.…”