Anti-CD8 antibodies can inhibit or enhance peptide-MHC class I (pMHCI) multimer binding: this is paralleled by their effects on CTL activation and occurs in the absence of an interaction between pMHCI and CD8 on the cell surface

Linda Wooldridge, Sarah L Hutchinson, Ed M Choi, Anya Lissina, Emma Jones, Fareed Mirza, P Rod Dunbar, David A Price, Vincenzo Cerundolo, Andy K Sewell

Research output: Contribution to journalArticle (Academic Journal)peer-review

42 Citations (Scopus)

Abstract

Cytotoxic T lymphocytes recognize short peptides presented in association with MHC class I (MHCI) molecules on the surface of target cells. The Ag specificity of T lymphocytes is conferred by the TCR, but invariable regions of the peptide-MHCI (pMHCI) molecule also interact with the cell surface glycoprotein CD8. The distinct binding sites for CD8 and the TCR allow pMHCI to be bound simultaneously by both molecules. Even before it was established that the TCR recognized pMHCI, it was shown that CTL exhibit clonal heterogeneity in their ability to activate in the presence of anti-CD8 Abs. These Ab-based studies have since been interpreted in the context of the interaction between pMHCI and CD8 and have recently been extended to show that anti-CD8 Ab can affect the cell surface binding of multimerized pMHCI Ags. In this study, we examine the role of CD8 further using point-mutated pMHCI Ag and show that anti-CD8 Abs can either enhance or inhibit the activation of CTL and the stable cell surface binding of multimerized pMHCI, regardless of whether there is a pMHCI/CD8 interaction. We further demonstrate that multimerized pMHCI Ag can recruit CD8 in the absence of a pMHCI/CD8 interaction and that anti-CD8 Abs can generate an intracellular activation signal resulting in CTL effector function. These results question many previous assumptions as to how anti-CD8 Abs must function and indicate that CD8 has multiple roles in CTL activation that are not necessarily dependent on an interaction with pMHCI.

Original languageEnglish
Pages (from-to)6650-60
Number of pages11
JournalJournal of Immunology
Volume171
Issue number12
Publication statusPublished - 15 Dec 2003

Keywords

  • Adjuvants, Immunologic
  • Animals
  • Antibodies, Blocking
  • Antigens, CD8
  • Binding Sites, Antibody
  • Binding, Competitive
  • Cell Line
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Membrane
  • Clone Cells
  • Cross-Linking Reagents
  • Cytotoxicity, Immunologic
  • H-2 Antigens
  • HLA-A2 Antigen
  • Histocompatibility Antigens Class I
  • Humans
  • Immunosuppressive Agents
  • Lymphocyte Activation
  • Mice
  • Peptides
  • Receptors, Antigen, T-Cell
  • T-Lymphocytes, Cytotoxic

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