title: A sharp T-cell antigen receptor signaling threshold for T-cell proliferation.
abstract: T-cell antigen receptor (TCR) signaling is essential for activation, proliferation, and effector function of T cells. Modulation of both intensity and duration of TCR signaling can regulate these events. However, it remains unclear how individual T cells integrate such signals over time to make critical cell-fate decisions. We have previously developed an engineered mutant allele of the critical T-cell kinase zeta-chain-associated protein kinase 70 kDa (Zap70) that is catalytically inhibited by a small molecule inhibitor, thereby blocking TCR signaling specifically and efficiently. We have also characterized a fluorescent reporter Nur77-eGFP transgenic mouse line in which T cells up-regulate GFP uniquely in response to TCR stimulation. The combination of these technologies unmasked a sharp TCR signaling threshold for commitment to cell division both in vitro and in vivo. Further, we demonstrate that this threshold is independent of both the magnitude of the TCR stimulus and Interleukin 2. Similarly, we identify a temporal threshold of TCR signaling that is required for commitment to proliferation, after which T cells are able to proliferate in a Zap70 kinase-independent manner. Taken together, our studies reveal a sharp threshold for the magnitude and duration of TCR signaling required for commitment of T cells to proliferation. These results have important implications for understanding T-cell responses to infection and optimizing strategies for immunomodulatory drug delivery.
authors.affiliation: Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine.
authors.forename: Byron B
authors.initials: BB
authors.lastname: Au-Yeung
authors.affiliation: Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine.
authors.forename: Julie
authors.initials: J
authors.lastname: Zikherman
authors.affiliation: Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine.
authors.forename: James L
authors.initials: JL
authors.lastname: Mueller
authors.affiliation: Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine.
authors.forename: Judith F
authors.initials: JF
authors.lastname: Ashouri
authors.affiliation: Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Matloubian
authors.affiliation: Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Cheng
authors.affiliation: Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cellular and Molecular Pharmacology, and Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.affiliation: Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Division of Rheumatology, Department of Medicine, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143 aweiss@medicine.ucsf.edu.
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D007376:Interleukin-2; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011948:Receptors, Antigen, T-Cell; D049452:Green Fluorescent Proteins; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse