title: TCR signal strength controls thymic differentiation of discrete proinflammatory γδ T cell subsets.
abstract: The mouse thymus produces discrete γδ T cell subsets that make either interferon-γ (IFN-γ) or interleukin 17 (IL-17), but the role of the T cell antigen receptor (TCR) in this developmental process remains controversial. Here we show that Cd3g(+/-) Cd3d(+/-) (CD3 double-haploinsufficient (CD3DH)) mice have reduced TCR expression and signaling strength on γδ T cells. CD3DH mice had normal numbers and phenotypes of αβ thymocyte subsets, but impaired differentiation of fetal Vγ6(+) (but not Vγ4(+)) IL-17-producing γδ T cells and a marked depletion of IFN-γ-producing CD122(+) NK1.1(+) γδ T cells throughout ontogeny. Adult CD3DH mice showed reduced peripheral IFN-γ(+) γδ T cells and were resistant to experimental cerebral malaria. Thus, TCR signal strength within specific thymic developmental windows is a major determinant of the generation of proinflammatory γδ T cell subsets and their impact on pathophysiology.
authors.affiliation: Department of Immunology, School of Medicine, Complutense University, Madrid, Spain.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Muñoz-Ruiz
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Ribot
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Grosso
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Natacha
authors.initials: N
authors.lastname: Gonçalves-Sousa
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Pamplona
authors.affiliation: Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Pennington
authors.affiliation: Department of Immunology, School of Medicine, Complutense University, Madrid, Spain.
authors.forename: José R
authors.initials: JR
authors.lastname: Regueiro
authors.affiliation: Department of Immunology, School of Medicine, Complutense University, Madrid, Spain.
authors.forename: Edgar
authors.initials: E
authors.lastname: Fernández-Malavé
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Silva-Santos
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000378:metabolism; D016779:Malaria, Cerebral / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000276:immunology*
chemical_list: D000950:Antigens, Ly; C508022:Il2rb protein, mouse; D020381:Interleukin-17; D053646:Interleukin-2 Receptor beta Subunit; C527211:Klrb1c protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B; D016692:Receptors, Antigen, T-Cell, gamma-delta; C000589613:T-cell receptor Vgamma6, mouse; D007371:Interferon-gamma