A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndromeDeng, Zimu;Chong, Zhenlu;Law, Christopher S.;Mukai, Kojiro;Ho, Frances O.;Martinu, Tereza;Backes, Bradley J.;Eckalbar, Walter L.;Taguchi, Tomohiko;Shum, Anthony K.
doi: 10.1084/jem.20201045pmid: 32725126
Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport. Missense mutations of the COPA WD40 domain impair binding and sorting of proteins targeted for ER retrieval, but how this causes disease remains unknown. Given the importance of COPA in Golgi–ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. We show that a defect in COPI transport causes ligand-independent activation of STING. Furthermore, SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi. Activated STING stimulates type I interferon–driven inflammation in CopaE241K/+ mice that is rescued in STING-deficient animals. Our results demonstrate that COPA maintains immune homeostasis by regulating STING transport at the Golgi. In addition, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease.
Requirements for cDC2 positioning in blood-exposed regions of the neonatal and adult spleenLiu, Dan;Wu, Jiaxi;An, Jinping;Cyster, Jason G.
doi: 10.1084/jem.20192300pmid: 32808016
The marginal zone (MZ) of the spleen contains multiple cell types that are involved in mounting rapid immune responses against blood-borne pathogens, including conventional dendritic cells (cDCs) and MZ B cells. MZ B cells develop later than other B cell types and are sparse in neonatal mice. Here, we show that cDC2s are abundant in the MZ of neonatal compared with adult mice. We find that conditions associated with reduced MZ B cell numbers in adult mice cause increased cDC2 occupancy of the MZ. Treatment with the S1PR1-modulating drug, FTY720, causes cDC2 movement into the MZ through the indirect mechanism of displacing MZ B cells into follicles. Splenic cDC2s express high amounts of α4β1 and αLβ2 integrins and depend on these integrins and the adaptor Talin for their retention in blood-exposed regions of the spleen. Splenic CD4 T cell activation by particulate antigens is increased in mice with higher cDC2 density in the MZ, including in neonatal mice. Our work establishes requirements for homeostatic cDC2 positioning in the spleen and provides evidence that localization in blood-exposed regions around the white pulp augments cDC2 capture of particulate antigens. We suggest that MZ positioning of cDC2s partially compensates for the lack of MZ B cells during the neonatal period.
Imaging resident and recruited macrophage contribution to Wallerian degenerationBoissonnas, Alexandre;Louboutin, Floriane;Laviron, Marie;Loyher, Pierre-Louis;Reboussin, Elodie;Barthelemy, Sandrine;Réaux-Le Goazigo, Annabelle;Lobsiger, Christian S.;Combadière, Béhazine;Mélik Parsadaniantz, Stéphane;Combadière, Christophe
doi: 10.1084/jem.20200471pmid: 32648893
Wallerian degeneration (WD) is a process of autonomous distal degeneration of axons upon injury. Macrophages (MPs) of the peripheral nervous system (PNS) are the main cellular agent controlling this process. Some evidence suggests that resident PNS-MPs along with MPs of hematogenous origin may be involved, but whether these two subsets exert distinct functions is unknown. Combining MP-designed fluorescent reporter mice and coherent anti–Stokes Raman scattering (CARS) imaging of the sciatic nerve, we deciphered the spatiotemporal choreography of resident and recently recruited MPs after injury and unveiled distinct functions of these subsets, with recruited MPs being responsible for efficient myelin stripping and clearance and resident MPs being involved in axonal regrowth. This work provides clues to tackle selectively cellular processes involved in neurodegenerative diseases.
Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s diseaseBarthélemy, Nicolas R.;Horie, Kanta;Sato, Chihiro;Bateman, Randall J.
doi: 10.1084/jem.20200861pmid: 32725127
Highly sensitive and specific plasma biomarkers for Alzheimer’s disease (AD) have the potential to improve diagnostic accuracy in the clinic and facilitate research studies including enrollment in prevention and treatment trials. We recently reported CSF tau hyperphosphorylation, especially on T217, is an accurate predictor of β-amyloidosis at asymptomatic and symptomatic stages. In the current study, we determine by mass spectrometry the potential utility of plasma p-tau isoforms to detect AD pathology and investigate CSF and plasma tau isoforms’ profile relationships. Plasma tau was truncated as previously described in CSF. CSF and plasma measures of p-tau-217 and p-tau-181 were correlated. No correlation was found between CSF and plasma on total-tau levels and pS202 measures. We found p-tau-217 and p-tau-181 were highly specific for amyloid plaque pathology in the discovery cohort (n = 36, AUROC = 0.99 and 0.98 respectively). In the validation cohort (n = 92), p-tau-217 measures were still specific to amyloid status (AUROC = 0.92), and p-tau-181 measures were less specific (AUROC = 0.75).
Charles E. Egwuagu: Going with the flowHouston, Stephanie
doi: 10.1084/jem.20202154pmid: 33095234
Charles E. Egwuagu is an epidemiologist/immunologist and chief of the Molecular Immunology Section at the National Eye Institute, National Institutes of Health, Bethesda, MD. His laboratory is focused on understanding the role played by lymphocytes in autoimmune diseases of the central nervous system. I chatted with Charles about his career so far.
Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infectionFumagalli, Valeria; Di Lucia, Pietro;Venzin, Valentina;Bono, Elisa B.;Jordan, Robert;Frey, Christian R.;Delaney, William;Chisari, Francis V.;Guidotti, Luca G.;Iannacone, Matteo
doi: 10.1084/jem.20200298pmid: 32761167
Antibody-mediated clearance of hepatitis B surface antigen (HBsAg) from the circulation of chronically infected patients (i.e., seroconversion) is usually associated with increased HBV-specific T cell responsiveness. However, a causative link between serum HBsAg levels and impairment of intrahepatic CD8+ T cells has not been established. Here we addressed this issue by using HBV replication-competent transgenic mice that are depleted of circulating HBsAg, via either spontaneous seroconversion or therapeutic monoclonal antibodies, as recipients of HBV-specific CD8+ T cells. Surprisingly, we found that serum HBsAg clearance has only a minimal effect on the expansion of HBV-specific naive CD8+ T cells undergoing intrahepatic priming. It does not alter their propensity to become dysfunctional, nor does it enhance the capacity of IL-2–based immunotherapeutic strategies to increase their antiviral function. In summary, our results reveal that circulating HBsAg clearance does not improve HBV-specific CD8+ T cell responses in vivo and may have important implications for the treatment of chronic HBV infection.