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¹ Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, 1066 Epalinges, Switzerland
² Centre d'Immunologie de Marseille-Luminy, Institut National de la Sante et de la Recherche Medicale, Centre National de la Recherche Scientifique, University of Marseille, Marseille 13288 Cedex 9, France
³ Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
⁴ Swiss Federal Institute of Technology, Lausanne 1015, Switzerland

Address correspondence to I.F. Luescher, Ludwig Institute, Lausanne Branch, Chemin des Boveresses 155, 1066 Epalinges, Switzerland. Phone: 41-21-692-5988; Fax: 41-21-653-4474; E-mail: iluesche{at}eliot.unil.ch

The extraordinary sensitivity of CD8⁺ T cells to recognize antigen impinges to a large extent on the coreceptor CD8. While several studies have shown that the CD8ß chain endows CD8 with efficient coreceptor function, the molecular basis for this is enigmatic. Here we report that cell-associated CD8ß, but not CD8 or soluble CD8ß, substantially increases the avidity of T cell receptor (TCR)-ligand binding. To elucidate how the cytoplasmic and transmembrane portions of CD8ß endow CD8 with efficient coreceptor function, we examined T1.4 T cell hybridomas transfected with various CD8ß constructs. T1.4 hybridomas recognize a photoreactive Plasmodium berghei circumsporozoite (PbCS) peptide derivative (PbCS (4-azidobezoic acid [ABA])) in the context of H-2K^d, and permit assessment of TCR-ligand binding by TCR photoaffinity labeling. We find that the cytoplasmic portion of CD8ß, mainly due to its palmitoylation, mediates partitioning of CD8 in lipid rafts, where it efficiently associates with p56^lck. In addition, the cytoplasmic portion of CD8ß mediates constitutive association of CD8 with TCR/CD3. The resulting TCR-CD8 adducts exhibit high affinity for major histocompatibility complex (MHC)-peptide. Importantly, because CD8ß partitions in rafts, its interaction with TCR/CD3 promotes raft association of TCR/CD3. Engagement of these TCR/CD3-CD8/lck adducts by multimeric MHC-peptide induces activation of p56^lck in rafts, which in turn phosphorylates CD3 and initiates T cell activation.

Key Words: T lymphocytes • cytotoxicity • phosphorylation • protein-tyrosine kinase • plasmon resonance

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