title: T cell expansion is the limiting factor of virus control in mice with attenuated TCR signaling: implications for human immunodeficiency.
abstract: Defining the minimal thresholds for effective antiviral T cell immunity is important for clinical decisions in immunodeficient patients. TCR signaling is critical for T cell development, activation, and effector functions. In this article, we analyzed which of these TCR-mediated processes is limiting for antiviral immunity in a mouse strain with reduced expression of SLP-76 (twp mice). Despite severe T cell activation defects in vitro, twp mice generated a normal proportion of antiviral effector T cells postinfection with lymphocytic choriomeningitis virus (LCMV). Twp CD8(+) T cells showed impaired polyfunctional cytokine production, whereas cytotoxicity as the crucial antiviral effector function for LCMV control was normal. The main limiting factor in the antiviral response of twp mice was impaired T cell proliferation and survival, leading to a 5- to 10-fold reduction of antiviral T cells at the peak of the immune response. This was still sufficient to control infection with the LCMV Armstrong strain, but the more rapidly replicating LCMV-WE induced T cell exhaustion and viral persistence. Thus, under conditions of impaired TCR signaling, reduced T cell expansion was the limiting factor in antiviral immunity. These findings have implications for understanding antiviral immunity in patients with T cell deficiencies.
authors: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, 79106 Freiburg, Germany; Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany;
authors: Kristina M
authors: KM
authors: Hillen
authors: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, 79106 Freiburg, Germany; Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany;
authors: Ruth
authors: R
authors: Gather
authors: Ramaciotti Immunization Genomics Laboratory, Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Acton 2601, Australian Capital Territory, Australia;
authors: Anselm
authors: A
authors: Enders
authors: Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, 79104 Freiburg, Germany;
authors: Hanspeter
authors: H
authors: Pircher
authors: Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, 79104 Freiburg, Germany;
authors: Peter
authors: P
authors: Aichele
authors: Institute of Pathology, University Medical Center Freiburg, 79106 Freiburg, Germany; and.
authors: Paul
authors: P
authors: Fisch
authors: Institute of Pathology, University Medical Center Freiburg, 79106 Freiburg, Germany; and.
authors: Britta
authors: B
authors: Blumenthal
authors: Institute of Pathology, University Medical Center Freiburg, 79106 Freiburg, Germany; and.
authors: Wolfgang W
authors: WW
authors: Schamel
authors: Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany;
authors: Tobias
authors: T
authors: Straub
authors: Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Acton 2601, Australian Capital Territory, Australia.
authors: Christopher C
authors: CC
authors: Goodnow
authors: Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, 79106 Freiburg, Germany; stephan.ehl@uniklinik-freiburg.de.
authors: Stephan
authors: S
authors: Ehl
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology* / Q000502:physiology; D008817:Mice, Mutant Strains; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins