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

Eur J Immunol. 2016 Sep;46(9):2121-36. doi: 10.1002/eji.201646331. Epub 2016 Jul 29.

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.

Keywords: ADAP; Cytokine; Integrin; iNKT cell; slp-76.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Biomarkers
  • C-Reactive Protein / genetics
  • C-Reactive Protein / metabolism
  • CD11b Antigen / genetics
  • CD11b Antigen / metabolism
  • Cytokines / biosynthesis*
  • Gene Deletion
  • Gene Expression
  • Hepatitis / etiology
  • Hepatitis / metabolism
  • Hepatitis / pathology
  • Inhibitor of Differentiation Proteins / genetics
  • Inhibitor of Differentiation Proteins / metabolism
  • Intercellular Adhesion Molecule-1 / metabolism
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Liver / immunology
  • Lymph Nodes / immunology
  • Lymphocyte Function-Associated Antigen-1 / genetics
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Mice
  • Mice, Knockout
  • Mutation*
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Organ Specificity / immunology
  • Phenotype
  • Phosphoproteins / chemistry
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Promyelocytic Leukemia Zinc Finger Protein
  • Protein Binding
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • Spleen / immunology
  • Thymus Gland / immunology
  • src Homology Domains / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • Biomarkers
  • CD11b Antigen
  • Cytokines
  • Fyb protein, mouse
  • Inhibitor of Differentiation Proteins
  • Kruppel-Like Transcription Factors
  • Lymphocyte Function-Associated Antigen-1
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Promyelocytic Leukemia Zinc Finger Protein
  • Receptors, Antigen, T-Cell
  • SLP-76 signal Transducing adaptor proteins
  • Zbtb16 protein, mouse
  • neuronal pentraxin
  • Intercellular Adhesion Molecule-1
  • Idb3 protein, mouse
  • C-Reactive Protein