title: Fine-tuning of CD8(+) T-cell effector functions by targeting the 2B4-CD48 interaction.
abstract: Polyfunctionality and cytotoxic activity dictate CD8(+) T-cell efficacy in the eradication of infected and malignant cells. The induction of these effector functions depends on the specific interaction between the T-cell receptor (TCR) and its cognate peptide-MHC class I complex, in addition to signals provided by co-stimulatory or co-inhibitory receptors, which can further regulate these functions. Among these receptors, the role of 2B4 is contested, as it has been described as either co-stimulatory or co-inhibitory in modulating T-cell functions. We therefore combined functional, transcriptional and epigenetic approaches to further characterize the impact of disrupting the interaction of 2B4 with its ligand CD48, on the activity of human effector CD8(+) T-cell clones. In this setting, we show that the 2B4-CD48 axis is involved in the fine-tuning of CD8(+) T-cell effector function upon antigenic stimulation. Blocking this interaction resulted in reduced CD8(+) T-cell clone-mediated cytolytic activity, together with a subtle drop in the expression of genes involved in effector function regulation. Our results also imply a variable contribution of the 2B4-CD48 interaction to the modulation of CD8(+) T-cell functional properties, potentially linked to intrinsic levels of T-bet expression and TCR avidity. The present study thus provides further insights into the role of the 2B4-CD48 interaction in the fine regulation of CD8(+) T-cell effector function upon antigenic stimulation.
authors: Sorbonne Universités, UPMC Univ Paris 06, DHU FAST, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.|INSERM U1135, CIMI-Paris, Paris, France.
authors: Anna
authors: A
authors: Lissina
authors: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: David R
authors: DR
authors: Ambrozak
authors: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Kristin L
authors: KL
authors: Boswell
authors: Systems Biology Center, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA.
authors: Wenjing
authors: W
authors: Yang
authors: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA.
authors: Eli
authors: E
authors: Boritz
authors: Systems Biology Center, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA.
authors: Yoshiyuki
authors: Y
authors: Wakabayashi
authors: Sorbonne Universités, UPMC Univ Paris 06, DHU FAST, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.|INSERM U1135, CIMI-Paris, Paris, France.
authors: Maria C
authors: MC
authors: Iglesias
authors: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors: Masao
authors: M
authors: Hashimoto
authors: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors: Masafumi
authors: M
authors: Takiguchi
authors: Vaccine and Gene Therapy Institute of Florida, Lucie, FL, USA.
authors: Elias
authors: E
authors: Haddad
authors: Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA.
authors: Daniel C
authors: DC
authors: Douek
authors: Systems Biology Center, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA.
authors: Jun
authors: 0000-0003-4573-8933
authors: J
authors: Zhu
authors: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Richard A
authors: RA
authors: Koup
authors: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Takuya
authors: T
authors: Yamamoto
authors: Sorbonne Universités, UPMC Univ Paris 06, DHU FAST, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.|INSERM U1135, CIMI-Paris, Paris, France.
authors: Victor
authors: V
authors: Appay
mesh_terms: D000915:Antibody Affinity / Q000276:immunology; D000071178:CD48 Antigen / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D044127:Epigenesis, Genetic; D006801:Humans; D056747:Immunomodulation; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor
chemical_list: C084093:CD244 protein, human; D000071178:CD48 Antigen; D011948:Receptors, Antigen, T-Cell; D000071176:Signaling Lymphocytic Activation Molecule Family; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor