A mutation within the SH2 domain of slp‐76 regulates the tissue distribution and cytokine production of iNKT cells in mice

Autor: Harald Arnold, Kasper Hoebe, Anna Katharina Koller, Annegret Reinhold, Swen Engelmann, Stephanie Schmidt, Sidonia Mihai, Christian Bogdan, Maike Willers, Christoph Daniel, Hans Parsch, Julia L.C. Baier, Robert Opoka, Stefanie Kliche, Claudia Giessler, Claudia Danzer, Stefan Wirtz, Jochen Mattner
Rok vydání: 2016
Předmět:
0301 basic medicine
medicine.medical_treatment
Gene Expression
Hepatitis
Mice
0302 clinical medicine
Immunology and Allergy
Promyelocytic Leukemia Zinc Finger Protein
Mice
Knockout
CD11b Antigen
biology
Signal transducing adaptor protein
Intercellular Adhesion Molecule-1
Lymphocyte Function-Associated Antigen-1
Cell biology
C-Reactive Protein
Phenotype
Cytokine
Liver
Organ Specificity
Concanavalin A
Cytokines
Lymph
medicine.symptom
Protein Binding
Signal Transduction
Nerve growth factor IB
Immunology
Kruppel-Like Transcription Factors
Receptors
Antigen
T-Cell
Nerve Tissue Proteins
Inflammation
Thymus Gland
src Homology Domains
03 medical and health sciences
medicine
Animals
Transcription factor
Adaptor Proteins
Signal Transducing
T-cell receptor
Phosphoproteins
030104 developmental biology
Mutation
biology.protein
Cancer research
Natural Killer T-Cells
Inhibitor of Differentiation Proteins
Lymph Nodes
Biomarkers
Gene Deletion
Spleen
030215 immunology
Zdroj: European Journal of Immunology. 46:2121-2136
ISSN: 1521-4141
0014-2980
DOI: 10.1002/eji.201646331
Popis: 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.
Databáze: OpenAIRE
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