title: The CD8 T cell coreceptor exhibits disproportionate biological activity at extremely low binding affinities.
abstract: T lymphocytes recognize peptides presented in the context of major histocompatibility complex (MHC) molecules on the surface of antigen presenting cells. Recognition specificity is determined by the alphabeta T cell receptor (TCR). The T lymphocyte surface glycoproteins CD8 and CD4 enhance T cell antigen recognition by binding to MHC class I and class II molecules, respectively. Biophysical measurements have determined that equilibrium binding of the TCR with natural agonist peptide-MHC (pMHC) complexes occurs with KD values of 1-50 microm. The pMHCI/CD8 and pMHCII/CD4 interactions are significantly weaker than this (KD >100 microm), and the relative roles of TCR/pMHC and pMHC/coreceptor affinity in T cell activation remain controversial. Here, we engineer mutations in the MHCI heavy chain and beta2-microglobulin that further reduce or abolish the pMHCI/CD8 interaction to probe the significance of pMHC/coreceptor affinity in T cell activation. We demonstrate that the pMHCI/CD8 coreceptor interaction retains the vast majority of its biological activity at affinities that are reduced by over 15-fold (KD > 2 mm). In contrast to previous reports, we observe that the weak interaction between HLA A68 and CD8, which falls within this spectrum of reduced affinities, retains substantial functional activity. These findings are discussed in the context of current concepts of coreceptor dependence and the mechanism by which TCR coreceptors facilitate T cell activation.
authors.affiliation: The T Cell Modulation Group, The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Hutchinson
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
authors.forename: Sabrina
authors.initials: S
authors.lastname: Tafuro
authors.forename: Bruno
authors.initials: B
authors.lastname: Laugel
authors.forename: Meir
authors.initials: M
authors.lastname: Glick
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Boulter
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
mesh_terms: D017951:Antigen Presentation / Q000235:genetics; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics
chemical_list: D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I