title: CD3 ligation on immature thymocytes generates antagonist-like signals appropriate for CD8 lineage commitment, independently of T cell receptor specificity.
abstract: The signals that direct differentiation of T cells to the CD4 or CD8 lineages in the thymus remain poorly understood. Although it has been relatively easy to direct differentiation of CD4 single positive (CD4+) cells using combinations of antibodies and pharmacological agents that mimic receptor engagements, equivalent stimuli do not induce efficient maturation of CD8+ cells. Here we report that, irrespective of the MHC-restriction specificity of the TCR, differentiation of mature CD8+ thymocytes can be induced by ligation of CD3 polypeptides on immature thymocytes with a F(ab')2 reagent (CD3fos-F(ab')2). The tyrosine phosphorylation patterns stimulated by CD3fos-F(ab')2 have been shown to resemble those delivered to mature T cells by antagonist peptides, which are known to direct positive selection of CD8+ cells, and we can show that this reagent exhibits potent antagonistic-like activity for primary T cell responses. Our results suggest a distinction in the signals that specify lineage commitment in the thymus. We present a model of thymocyte differentiation that proposes that the relative balance of signals delivered by TCR engagement and by p56lck activation is responsible for directing commitment to the CD8 or CD4 lineages.
authors.affiliation: Division of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom.
authors.forename: M A
authors.initials: MA
authors.lastname: Basson
authors.forename: U
authors.initials: U
authors.lastname: Bommhardt
authors.forename: M S
authors.initials: MS
authors.lastname: Cole
authors.forename: J Y
authors.initials: JY
authors.lastname: Tso
authors.forename: R
authors.initials: R
authors.lastname: Zamoyska
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D019070:Cell Lineage; D003601:Cytotoxicity Tests, Immunologic; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006649:Histocompatibility Antigens; D007128:Immunoglobulin Fragments / Q000276:immunology; D007152:Immunologic Capping; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D017252:CD3 Complex; C111990:CD3fos-F(ab')2; D006649:Histocompatibility Antigens; D007128:Immunoglobulin Fragments; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse