title: A mutation within the SH2 domain of slp-76 regulates the tissue distribution and cytokine production of iNKT cells in mice.
abstract: TCR ligation is critical for the selection, activation, and integrin expression of T lymphocytes. Here, we explored the role of the TCR adaptor protein slp-76 on iNKT-cell biology. Compared to B6 controls, slp-76(ace/ace) mice carrying a missense mutation (Thr428Ile) within the SH2-domain of slp-76 showed an increase in iNKT cells in the thymus and lymph nodes, but a decrease in iNKT cells in spleens and livers, along with reduced ADAP expression and cytokine response. A comparable reduction in iNKT cells was observed in the livers and spleens of ADAP-deficient mice. Like ADAP(-/-) iNKT cells, slp-76(ace/ace) iNKT cells were characterized by enhanced CD11b expression, correlating with an impaired induction of the TCR immediate-early gene Nur77 and a decreased adhesion to ICAM-1. Furthermore, CD11b-intrinsic effects inhibited cytokine release, concanavalin A-mediated inflammation, and iNKT-cell accumulation in the liver. Unlike B6 and ADAP(-/-) mice, the expression of the transcription factors Id3 and PLZF was reduced, whereas NP-1-expression was enhanced in slp-76(ace/ace) mice. Blockade of NP-1 decreased the recovery of iNKT cells from peripheral lymph nodes, identifying NP-1 as an iNKT-cell-specific adhesion factor. Thus, slp-76 contributes to the regulation of the tissue distribution, PLZF, and cytokine expression of iNKT cells via ADAP-dependent and -independent mechanisms.
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Danzer
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Koller
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Baier
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Arnold
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Giessler
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Opoka
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Willers
authors.affiliation: Zentrallabor, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Sidonia
authors.initials: S
authors.lastname: Mihai
authors.affiliation: Zentrallabor, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Parsch
authors.affiliation: Medizinische Klinik 1, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.affiliation: Nephropathologische Abteilung, Universitätsklinikum Erlangen and Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Daniel
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Reinhold
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Swen
authors.initials: S
authors.lastname: Engelmann
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kliche
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bogdan
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
authors.forename: Kasper
authors.initials: K
authors.lastname: Hoebe
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany. Jochen.Mattner@uk-erlangen.de.|Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH, USA. Jochen.Mattner@uk-erlangen.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Mattner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D017353:Gene Deletion; D015870:Gene Expression; D006505:Hepatitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity / Q000276:immunology; D010641:Phenotype; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D018909:src Homology Domains / Q000235:genetics*; D000099153:Pentraxins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D002097:C-Reactive Protein; D039481:CD11b Antigen; D016207:Cytokines; D051796:Inhibitor of Differentiation Proteins; D018799:Intercellular Adhesion Molecule-1; D051741:Kruppel-Like Transcription Factors; D016169:Lymphocyte Function-Associated Antigen-1; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011948:Receptors, Antigen, T-Cell; D000099153:Pentraxins; C491468:Fyb protein, mouse; C092947:SLP-76 signal Transducing adaptor proteins; C513267:Zbtb16 protein, mouse; C067679:Idb3 protein, mouse
keywords: ADAP; Cytokine; Integrin; iNKT cell; slp-76