title: A novel postpriming regulatory check point of effector/memory T cells dictated through antigen density threshold-dependent anergy.
abstract: CTLs act as the effector arm of the cell-mediated immune system to kill undesirable cells. Two processes regulate these effector cells to prevent self reactivity: a thymic selection process that eliminates autoreactive clones and a multistage activation or priming process that endows them with a license to kill cognate target cells. Hitherto no subsequent regulatory restrictions have been ascribed for properly primed and activated CTLs that are licensed to kill. In this study we show that CTLs possess a novel postpriming regulatory mechanism(s) that influences the outcome of their encounter with cognate target cells. This mechanism gauges the degree of Ag density, whereupon reaching a certain threshold significant changes occur that induce anergy in the effector T cells. The biological consequences of this Ag-induced postpriming control includes alterations in the expression of cell surface molecules that control immunological synapse activity and cytokine profiles and induce retarded cell proliferation. Most profound is genome-wide microarray analysis that demonstrates changes in the expression of genes related to membrane potential, TCR signal transduction, energy metabolism, and cell cycle control. Thus, a discernible and unique gene expression signature for anergy as a response to high Ag density has been observed. Consequently, activated T cells possess properties of a self-referential sensory organ. These studies identify a new postpriming control mechanism of CTL with anergenic-like properties. This mechanism extends our understanding of the control of immune function and regulation such as peripheral tolerance, viral infections, antitumor immune responses, hypersensitivity, and autoimmunity.
authors.affiliation: Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Kfir
authors.initials: K
authors.lastname: Oved
authors.forename: Omer
authors.initials: O
authors.lastname: Ziv
authors.forename: Jasmine
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: Roy
authors.initials: R
authors.lastname: Noy
authors.forename: Hila
authors.initials: H
authors.lastname: Novak
authors.forename: Oryan
authors.initials: O
authors.lastname: Makler
authors.forename: Denkberg
authors.initials: D
authors.lastname: Galit
authors.forename: Sinik
authors.initials: S
authors.lastname: Keren
authors.forename: Dina
authors.initials: D
authors.lastname: Segal
authors.forename: Chen
authors.initials: C
authors.lastname: Gefen-Dor
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Yoram
authors.initials: Y
authors.lastname: Reiter
mesh_terms: D000941:Antigens / Q000276:immunology*; D045744:Cell Line, Tumor; D017635:Clonal Anergy / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000941:Antigens; D016207:Cytokines