title: Vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) provide co-stimulation in positive selection along with survival of selected thymocytes.
abstract: T-cell differentiation in the thymus depends on positive selection of CD4+CD8+ double positive (DP) thymocytes by thymic major histocompatibility complex (MHC) molecules. Positive selection allows maturation of only those thymocytes that are capable of self-peptide-MHC recognition. Thymocytes that fail to bind self-peptide-MHC die by apoptosis. An important question in thymocyte differentiation is whether co-stimulation is required for positive selection and on which cells co-stimulatory molecules may be expressed in the thymus. The vascular cell adhesion molecule (VCAM-1) and the intercellular cell adhesion molecule (ICAM-1) are known to be potent co-stimulatory molecules in activation of peripheral T-cells by interacting with the integrins VLA-4 and LFA-1, respectively. We were prompted to investigate whether VCAM-1 and ICAM-1 may also act as co-stimulators during selection of thymocytes. By using recombinant proteins of murine VCAM-1 and ICAM-1 fused to the Fc region of human IgG1 (rVCAM-1, rICAM-1) we examined the capacity of VCAM-1 and ICAM-1 to act as co-stimulatory molecules in positive selection in vitro. Triggering the CD3/TCR complex together with co-stimulation applied by rVCAM-1 or rICAM-1 induced the generation of CD4+ single positive (SP) thymocytes from CD4+CD8+ DP thymocytes whereas either signal alone did not result in generation of CD4+ SP thymocytes. VCAM-1 and ICAM-1 act therefore as co-stimulatory molecules in thymocyte positive selection in vitro. The generation of CD4+ SP cells is accompanied by cell survival both when it was co-stimulated with rVCAM-1 and with rICAM-1. Importantly we show here that VCAM-1 expression in the murine thymus is restricted to cortical F4/80 positive hematopoietic antigen presenting cells (hAPC) present exclusively in the cortex whereas expression of ICAM-1 has been reported on the epithelium both in cortex and medulla. This suggests that not only the cortical epithelium may use the co-stimulatory molecule ICAM-1 to mediate positive selection, but also cortical hAPCs may contribute to positive selection of thymocytes by using the co-stimulator VCAM-1.
authors.affiliation: Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands. lutzpaessens@hotmail.com
authors.forename: Lutz C
authors.initials: LC
authors.lastname: Paessens
authors.forename: Satwinder K
authors.initials: SK
authors.lastname: Singh
authors.forename: Rosette J
authors.initials: RJ
authors.lastname: Fernandes
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D006413:Hematopoietic System / Q000166:cytology / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012641:Selection, Genetic; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000906:Antibodies; D002070:Butadienes; D017252:CD3 Complex; D009570:Nitriles; D011948:Receptors, Antigen, T-Cell; C113580:U 0126; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D020929:Mitogen-Activated Protein Kinase Kinases