title: Notch controls the magnitude of T helper cell responses by promoting cellular longevity.
abstract: Generation of effective immune responses requires expansion of rare antigen-specific CD4(+) T cells. The magnitude of the responding population is ultimately determined by proliferation and survival. Both processes are tightly controlled to limit responses to innocuous antigens. Sustained expansion occurs only when innate immune sensors are activated by microbial stimuli or by adjuvants, which has important implications for vaccination. The molecular identity of the signals controlling sustained T-cell responses is not fully clear. Here, we describe a prominent role for the Notch pathway in this process. Coactivation of Notch allows accumulation of far greater numbers of activated CD4(+) T cells than stimulation via T-cell receptor and classic costimulation alone. Notch does not overtly affect cell cycle entry or progression of CD4(+) T cells. Instead, Notch protects activated CD4(+) T cells against apoptosis after an initial phase of clonal expansion. Notch induces a broad antiapoptotic gene expression program that protects against intrinsic, as well as extrinsic, apoptosis pathways. Both Notch1 and Notch2 receptors and the canonical effector RBPJ (recombination signal binding protein for immunoglobulin kappa J region) are involved in this process. Correspondingly, CD4(+) T-cell responses to immunization with protein antigen are strongly reduced in mice lacking these components of the Notch pathway. Our findings, therefore, show that Notch controls the magnitude of CD4(+) T-cell responses by promoting cellular longevity.
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, 1105AZ Amsterdam, The Netherlands.
authors.forename: Christina
authors.initials: C
authors.lastname: Helbig
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gentek
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Backer
authors.forename: Yevan
authors.initials: Y
authors.lastname: de Souza
authors.forename: Ingrid A M
authors.initials: IA
authors.lastname: Derks
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
authors.forename: Koen
authors.initials: K
authors.lastname: Wagner
authors.forename: Dragana
authors.initials: D
authors.lastname: Jankovic
authors.forename: Thomas
authors.initials: T
authors.lastname: Gridley
authors.forename: Perry D
authors.initials: PD
authors.lastname: Moerland
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Derk
authors.initials: D
authors.lastname: Amsen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology / Q000502:physiology; D005434:Flow Cytometry; D006433:Hemocyanins; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D051880:Receptors, Notch; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin