title: TCR comodulation of nonengaged TCR takes place by a protein kinase C and CD3 gamma di-leucine-based motif-dependent mechanism.
abstract: One of the earliest events following TCR triggering is TCR down-regulation. However, the mechanisms behind TCR down-regulation are still not fully known. Some studies have suggested that only directly triggered TCR are internalized, whereas others studies have indicated that, in addition to triggered receptors, nonengaged TCR are also internalized (comodulated). In this study, we used transfected T cells expressing two different TCR to analyze whether comodulation took place. We show that TCR triggering by anti-TCR mAb and peptide-MHC complexes clearly induced internalization of nonengaged TCR. By using a panel of mAb against the Ti beta chain, we demonstrate that the comodulation kinetics depended on the affinity of the ligand. Thus, high-affinity mAb (K(D) = 2.3 nM) induced a rapid but reversible comodulation, whereas low-affinity mAb (K(D) = 6200 nM) induced a slower but more permanent type of comodulation. Like internalization of engaged TCR, comodulation was dependent on protein tyrosine kinase activity. Finally, we found that in contrast to internalization of engaged TCR, comodulation was highly dependent on protein kinase C activity and the CD3 gamma di-leucine-based motif. Based on these observations, a physiological role of comodulation is proposed and the plausibility of the TCR serial triggering model is discussed.
authors.affiliation: Institute of Medical Microbiology and Immunology, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Charlotte Menné
authors.initials: CM
authors.lastname: Bonefeld
authors.forename: Anette B
authors.initials: AB
authors.lastname: Rasmussen
authors.forename: Jens Peter H
authors.initials: JP
authors.lastname: Lauritsen
authors.forename: Marina
authors.initials: M
authors.lastname: von Essen
authors.forename: Niels
authors.initials: N
authors.lastname: Ødum
authors.forename: Peter S
authors.initials: PS
authors.lastname: Andersen
authors.forename: Carsten
authors.initials: C
authors.lastname: Geisler
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000918:Antibody Specificity; D017252:CD3 Complex / Q000502:physiology*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D007930:Leucine / Q000502:physiology*; D008024:Ligands; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D011493:Protein Kinase C / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; C452842:CD3 antigen, gamma chain; D004151:Dipeptides; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D007930:Leucine