title: T cell signaling. Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion.
abstract: T cell responses are initiated by antigen and promoted by a range of costimulatory signals. Understanding how T cells integrate alternative signal combinations and make decisions affecting immune response strength or tolerance poses a considerable theoretical challenge. Here, we report that T cell receptor (TCR) and costimulatory signals imprint an early, cell-intrinsic, division fate, whereby cells effectively count through generations before returning automatically to a quiescent state. This autonomous program can be extended by cytokines. Signals from the TCR, costimulatory receptors, and cytokines add together using a linear division calculus, allowing the strength of a T cell response to be predicted from the sum of the underlying signal components. These data resolve a long-standing costimulation paradox and provide a quantitative paradigm for therapeutically manipulating immune response strength.
authors.affiliation: Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Marchingo
authors.affiliation: Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Andrey
authors.initials: A
authors.lastname: Kan
authors.affiliation: Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Sutherland
authors.affiliation: Hamilton Institute, National University of Ireland, Maynooth, Ireland.
authors.forename: Ken R
authors.initials: KR
authors.lastname: Duffy
authors.affiliation: Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Wellard
authors.affiliation: Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
authors.affiliation: Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. The Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Dowling
authors.affiliation: Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Susanne
authors.initials: S
authors.lastname: Heinzel
authors.affiliation: Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. hodgkin@wehi.edu.au.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Hodgkin
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002455:Cell Division; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology*; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D000941:Antigens; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell