title: Persistent viral infection in humans can drive high frequency low-affinity T-cell expansions.
abstract: CD8 T cells that recognize cytomegalovirus (CMV) -encoded peptides can be readily detected by staining with human leucocyte antigen (HLA) -peptide tetramers. These cells are invariably highly differentiated effector memory cells with high avidity T-cell receptors (TCR). In this report we demonstrate an HLA-A*0201 restricted CMV-specific CD8 T-cell response (designated YVL) that represents several percent of the CD8 T-cell subset, yet fails to bind tetrameric major histocompatibility complex (MHC) ligands. However, these tetramer-negative cells are both phenotypically and functionally similar to other CMV-specific CD8 T cells. YVL peptide-specific CD8 T-cell clones were generated and found to be of high avidity in both cytotoxicity and interferon-γ (IFN-γ) assays, and comparable with other CMV peptide-specific CD8 T-cell clones. However, under conditions of CD8 blockade, the response was almost nullified even at very high ligand concentrations. This was also the case in IFN-γ experiments using peripheral blood mononuclear cells stimulated with peptide ex vivo. In contrast, all other CMV specificities (tetramer-positive) displayed minimal or only partial CD8 dependence. This suggests that YVL-specific responses depict a low-affinity TCR-MHC-peptide interaction, that is compensated by substantial CD8 involvement for functional purposes, yet cannot engage multivalent soluble ligands for ex vivo analysis. It is interesting that such a phenomenon is apparent in the face of a persistent virus infection such as CMV, where the responding cells represent an immunodominant response in that individual and may present a highly differentiated effector phenotype.
authors: Division of Immunology, School of Infection & Host Defence, University Of Liverpool, Daulby Street, Liverpool, UK. nkhan@liv.ac.uk
authors: Naeem
authors: N
authors: Khan
authors: Mark
authors: M
authors: Cobbold
authors: Joanne
authors: J
authors: Cummerson
authors: Paul A H
authors: PA
authors: Moss
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology / Q000494:pharmacology
chemical_list: D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; D007371:Interferon-gamma