title: CXCR3 expression defines a novel subset of innate CD8+ T cells that enhance immunity against bacterial infection and cancer upon stimulation with IL-15.
abstract: Innate CD8(+) T cells are a heterogeneous population with developmental pathways distinct from conventional CD8(+) T cells. However, their biology, classification, and functions remain incompletely understood. We recently demonstrated the existence of a novel population of chemokine (C-X-C motif) receptor 3 (CXCR3)-positive innate CD8(+) T cells. Here, we investigated the functional properties of this subset and identified effector molecules and pathways which mediate their function. Adoptive transfer of IL-15 activated CXCR3(+) innate CD8(+) T cells conferred increased protection against Listeria monocytogenes infection in susceptible IFN-γ(-/-) mice compared with similarly activated CXCR3(-) subset. This was associated with enhanced proliferation and IFN-γ production in CXCR3(+) cells. Further, CXCR3(+) innate cells showed enhanced cytotoxicity against a tumor cell line in vitro. In depth analysis of the CXCR3(+) subset showed increased gene expression of Ccl5, Klrc1, CtsW, GP49a, IL-2Rβ, Atp5e, and Ly6c but reduced IFN-γR2 and Art2b. Ingenuity pathway analysis revealed an up-regulation of genes associated with T-cell activation, proliferation, cytotoxicity, and translational initiation in CXCR3(+) populations. Our results demonstrate that CXCR3 expression in innate CD8(+) T cells defines a subset with enhanced cytotoxic potential and protective antibacterial immune functions. Immunotherapeutic approaches against infectious disease and cancer could utilize CXCR3(+) innate CD8(+) T-cell populations as novel clinical intervention strategies.
authors.affiliation: *Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio, USA; Department of Oral Biology, The Ohio State University College of Dentistry, Columbus, Ohio, USA; and Department of Microbiology, Center for Biostatistics, and Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Oghumu
authors.affiliation: *Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio, USA; Department of Oral Biology, The Ohio State University College of Dentistry, Columbus, Ohio, USA; and Department of Microbiology, Center for Biostatistics, and Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Terrazas
authors.affiliation: *Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio, USA; Department of Oral Biology, The Ohio State University College of Dentistry, Columbus, Ohio, USA; and Department of Microbiology, Center for Biostatistics, and Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Varikuti
authors.affiliation: *Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio, USA; Department of Oral Biology, The Ohio State University College of Dentistry, Columbus, Ohio, USA; and Department of Microbiology, Center for Biostatistics, and Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kimble
authors.affiliation: *Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio, USA; Department of Oral Biology, The Ohio State University College of Dentistry, Columbus, Ohio, USA; and Department of Microbiology, Center for Biostatistics, and Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Vadia
authors.affiliation: *Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio, USA; Department of Oral Biology, The Ohio State University College of Dentistry, Columbus, Ohio, USA; and Department of Microbiology, Center for Biostatistics, and Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.affiliation: *Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio, USA; Department of Oral Biology, The Ohio State University College of Dentistry, Columbus, Ohio, USA; and Department of Microbiology, Center for Biostatistics, and Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Seveau
authors.affiliation: *Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio, USA; Department of Oral Biology, The Ohio State University College of Dentistry, Columbus, Ohio, USA; and Department of Microbiology, Center for Biostatistics, and Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA abhay.satoskar@osumc.edu.
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D019070:Cell Lineage; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000502:physiology*; D019409:Interleukin-15 / Q000494:pharmacology*; D008089:Listeria monocytogenes / Q000472:pathogenicity; D008088:Listeriosis / Q000139:chemically induced / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000382:microbiology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054367:Receptors, CXCR3 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; C515188:Cxcr3 protein, mouse; D019409:Interleukin-15; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D007371:Interferon-gamma
keywords: Listeria; cytokine; cytotoxicity; granzyme; interferon