title: CRACC-targeting Fc-fusion protein induces activation of NK cells and DCs and improves T cell immune responses to antigenic targets.
abstract: The CD2-like receptor activating cytotoxic cell (CRACC) receptor is a member of the SLAM family of receptors that are found on several types of immune cells. We previously demonstrated that increasing the abundance of the adaptor protein EAT-2 during vaccination enhanced innate and adaptive immune responses to vaccine antigens. Engagement of the CRACC receptor in the presence of the EAT-2 adaptor generally results in immune cell activation, while activating CRACC signaling in cells that lack EAT-2 adaptor inhibits their effector and regulatory functions. As EAT-2 is the only SAP adaptor that interacts with the CRACC receptor, we hypothesized that technologies that specifically modulate CRACC signaling during vaccination may also improve antigen specific adaptive immune responses. To test this hypothesis, we constructed a CRACC-targeting Fc fusion protein and included it in vaccination attempts. Indeed, mice co-vaccinated with the CRACC-Fc fusion protein and an adenovirus vaccine expressing the HIV-Gag protein had improved Gag-specific T cell responses, as compared to control mice. These responses are characterized by increased numbers of Gag-specific tetramer+ CD8+ T cells and increases in production of IFNγ, TNFα, and IL2, by Gag-specific CD8+ T cells. Moreover, our results revealed that use of the CRACC-Fc fusion protein enhances vaccine-elicited innate immune responses, as characterized by increased dendritic cells (DCs) maturation and IFNγ production from NK cells. This study highlights the importance of CRACC signaling during the induction of an immune response generally, and during vaccinations specifically, and also lends insight into the mechanisms underlying our prior results noting EAT-2-dependent improvements in vaccine efficacy.
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Aldhamen
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
authors.forename: David P W
authors.initials: DPW
authors.lastname: Rastall
authors.affiliation: Center for Integrative Toxicology, Michigan State University, East Lansing, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Seregin
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
authors.forename: Cristiane
authors.initials: C
authors.lastname: Pereira-Hicks
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Godbehere
authors.affiliation: Center for Integrative Toxicology, Michigan State University, East Lansing, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA; Department of Pediatrics, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA. Electronic address: amalfit1@msu.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D000067996:RAW 264.7 Cells; D011993:Recombinant Fusion Proteins / Q000276:immunology; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D016207:Cytokines; D011993:Recombinant Fusion Proteins; C103572:SH2D1B protein, human; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; D014157:Transcription Factors
keywords: CD8+ T cells; CRACC receptor; DCs; EAT-2; Immune modulation; NK cells; SLAM