title: Pathogen-specific inflammatory milieux tune the antigen sensitivity of CD8(+) T cells by enhancing T cell receptor signaling.
abstract: CD8(+) T cells confer host protection through T-cell-receptor (TCR)-mediated recognition of foreign antigens presented by infected cells. Thus, generation of CD8(+) T cell populations with high antigen sensitivity is critical for efficient pathogen clearance. Besides selection of high-affinity TCRs, the molecular mechanisms regulating the antigen sensitivity of CD8(+) T cells remain poorly defined. Herein, we have demonstrated that the antigen sensitivity of effector and memory CD8(+) T cells is dynamically regulated and can be tuned by pathogen-induced inflammatory milieux independently of the selection of cells with higher TCR affinity. Mechanistically, we have demonstrated that the signal-transduction capacity of key TCR proximal molecules is enhanced by inflammatory cytokines, which reduced the antigen density required to trigger antimicrobial functions. Dynamic tuning of CD8(+) T cell antigen sensitivity by inflammatory cytokines most likely optimizes immunity to specific pathogens while minimizing the risk of immunopathology at steady state.
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Richer
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Nolz
authors.forename: John T
authors.initials: JT
authors.lastname: Harty
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D060966:Clonal Selection, Antigen-Mediated; D016207:Cytokines / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte; D007156:Immunologic Memory; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism*; D018836:Inflammation Mediators / Q000276:immunology; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000941:Antigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D018836:Inflammation Mediators; D011948:Receptors, Antigen, T-Cell