TY - JOUR
T1 - Spatiotemporal regulation of type I interferon expression determines the antiviral polarization of CD4(+) T cells
AU - De Giovanni, Marco
AU - Cutillo, Valeria
AU - Giladi, Amir
AU - Sala, Eleonora
AU - Maganuco, Carmela G.
AU - Medaglia, Chiara
AU - Di Lucia, Pietro
AU - Bono, Elisa
AU - Cristofani, Claudia
AU - Consolo, Eleonora
AU - Giustini, Leonardo
AU - Fiore, Alessandra
AU - Eickhoff, Sarah
AU - Kastenmueller, Wolfgang
AU - Amit, Ido
AU - Kuka, Mirela
AU - Iannacone, Matteo
N1 - We thank M. Mainetti and M. Freschi for technical support; M. Silva for secretarial assistance; J.C. de la Torre (The Scripps Research Institute) for providing rLCMV; D. Pinschewer (University of Basel) for providing rVSV; M. Linterman (Babraham Institute) for providing Cd11c-Cre; Ifnar1fl/fl bone marrow; R. Pardi and A. Mondino for critical reading of the manuscript; and the members of the Iannacone laboratory for helpful discussions. Confocal immunofluorescence histology was carried out at Alembic, San Raffaele Scientific Institute, and the Vita-Salute San Raffaele University. Flow cytometry was carried out at FRACTAL, San Raffaele Scientific Institute. We would like to acknowledge the PhD program in Basic and Applied Immunology and Oncology at Vita-Salute San Raffaele University, as V.C. and E.S. conducted this study as partial fulfillment of their PhD in Molecular Medicine within this program. M.I. is supported by European Research Council (ERC) Consolidator grant 725038, Italian Association for Cancer Research (AIRC) grants 19891 and 22737, Italian Ministry of Health (MoH) grant GR-2011-02347925, Lombardy Foundation for Biomedical Research (FRRB) grant 2015-0010, the European Molecular Biology Organization Young Investigator Program and a Career Development award from the Giovanni Armenise-Harvard Foundation. M.K. is supported by Italian Ministry of Education grants SIR-RBSI14BAO5 and PRIN-2017ZXT5WR. Contributions M.D.G., V.C. and M.K. designed and performed experiments, analyzed data, performed the statistical analyses and drafted the manuscript. E.S., C.G.M., P.D.L., E.B., C.C., E.C., L.G. and A.F. performed experiments and analyzed data. A.G., C.M. and I.A. performed the NICHE-seq and scRNA-seq analyses and prepared the related figures. S.E. and W.K. performed the Xcr1-DTR experiments and analyzed data. M.K. provided funding, conceptual advice and supervision. M.I. designed and coordinated the study, provided funding and wrote the manuscript.
PY - 2020/2/17
Y1 - 2020/2/17
N2 - Iannacone and colleagues show that the spatiotemporal regulation of type I interferon expression shapes the differentiation of antiviral CD4(+) T cells into T-FH or T(H)1 cells.Differentiation of CD4(+) T cells into either follicular helper T (T-FH) or type 1 helper T (T(H)1) cells influences the balance between humoral and cellular adaptive immunity, but the mechanisms whereby pathogens elicit distinct effector cells are incompletely understood. Here we analyzed the spatiotemporal dynamics of CD4(+) T cells during infection with recombinant vesicular stomatitis virus (VSV), which induces early, potent neutralizing antibodies, or recombinant lymphocytic choriomeningitis virus (LCMV), which induces a vigorous cellular response but inefficient neutralizing antibodies, expressing the same T cell epitope. Early exposure of dendritic cells to type I interferon (IFN), which occurred during infection with VSV, induced production of the cytokine IL-6 and drove T-FH cell polarization, whereas late exposure to type I IFN, which occurred during infection with LCMV, did not induce IL-6 and allowed differentiation into T(H)1 cells. Thus, tight spatiotemporal regulation of type I IFN shapes antiviral CD4(+) T cell differentiation and might instruct vaccine design strategies.
AB - Iannacone and colleagues show that the spatiotemporal regulation of type I interferon expression shapes the differentiation of antiviral CD4(+) T cells into T-FH or T(H)1 cells.Differentiation of CD4(+) T cells into either follicular helper T (T-FH) or type 1 helper T (T(H)1) cells influences the balance between humoral and cellular adaptive immunity, but the mechanisms whereby pathogens elicit distinct effector cells are incompletely understood. Here we analyzed the spatiotemporal dynamics of CD4(+) T cells during infection with recombinant vesicular stomatitis virus (VSV), which induces early, potent neutralizing antibodies, or recombinant lymphocytic choriomeningitis virus (LCMV), which induces a vigorous cellular response but inefficient neutralizing antibodies, expressing the same T cell epitope. Early exposure of dendritic cells to type I interferon (IFN), which occurred during infection with VSV, induced production of the cytokine IL-6 and drove T-FH cell polarization, whereas late exposure to type I IFN, which occurred during infection with LCMV, did not induce IL-6 and allowed differentiation into T(H)1 cells. Thus, tight spatiotemporal regulation of type I IFN shapes antiviral CD4(+) T cell differentiation and might instruct vaccine design strategies.
UR - http://www.scopus.com/inward/record.url?scp=85079817317&partnerID=8YFLogxK
U2 - 10.1038/s41590-020-0596-6
DO - 10.1038/s41590-020-0596-6
M3 - مقالة
SN - 1529-2908
VL - 21
SP - 321
EP - 330
JO - Nature Immunology
JF - Nature Immunology
IS - 3
ER -