title: Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection.
abstract: Sustained Ag persistence in chronic infection results in a deregulated CD8(+) T cell response that is characterized by T cell exhaustion and cell death of Ag-specific CD8(+) T cells. Yet, the underlying transcriptional mechanisms regulating CD8(+) T cell exhaustion and cell death are poorly defined. Using the experimental mouse model of lymphocytic choriomeningitis virus infection, we demonstrate that the transcriptional regulator Id3 controls cell death of virus-specific CD8(+) T cells in chronic infection. By comparing acute and chronic infection, we showed that Id3 (-) virus-specific CD8(+) T cells were less abundant, whereas the absolute numbers of Id3 (+) virus-specific CD8(+) T cells were equal in chronic and acute infection. Phenotypically, Id3 (-) and Id3 (+) cells most prominently differed with regard to expression of the surface receptor 2B4; although Id3 (-) cells were 2B4(+), almost all Id3 (+) cells lacked expression of 2B4. Lineage-tracing experiments showed that cells initially expressing Id3 differentiated into Id3 (-)2B4(+) cells; in turn, these cells were terminally differentiated and highly susceptible to cell death under conditions of persisting Ag. Enforced Id3 expression specifically increased the persistence of 2B4(+) virus-specific CD8(+) T cells by decreasing susceptibility to Fas/Fas ligand-mediated cell death. Thus, our findings reveal that the transcriptional regulator Id3 promotes the survival of virus-specific CD8(+) T cells in chronic infection and suggest that targeting Id3 might be beneficial for preventing cell death of CD8(+) T cells in chronic infection or for promoting cell death of uncontrolled, hyperactive CD8(+) T cells to prevent immunopathology.
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, 79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79106 Freiburg, Germany;
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Menner
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, 79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79106 Freiburg, Germany;
authors.forename: Katharina S
authors.initials: KS
authors.lastname: Rauch
authors.affiliation: Center for Microbiology and Hygiene, Institute for Immunology, University Medical Center and University of Freiburg, 79104 Freiburg, Germany; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Aichele
authors.affiliation: Center for Microbiology and Hygiene, Institute for Immunology, University Medical Center and University of Freiburg, 79104 Freiburg, Germany; and.
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Pircher
authors.affiliation: Department of Molecular Embryology, Institute of Anatomy and Cell Biology, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schachtrup
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, 79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79106 Freiburg, Germany; kristina.schachtrup@uniklinik-freiburg.de.
authors.forename: Kristina
authors.initials: K
authors.lastname: Schachtrup
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002908:Chronic Disease; D004285:Dogs; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology* / Q000502:physiology; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000071176:Signaling Lymphocytic Activation Molecule Family; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C490007:Cd244a protein, mouse; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D051796:Inhibitor of Differentiation Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D019014:fas Receptor; C067679:Idb3 protein, mouse