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

Claudia Danzer, Anna Koller, Julia Baier, Harald Arnold, Claudia Giessler, Robert Opoka, Stephanie Schmidt, Maike Willers, Sidonia Mihai, Hans Parsch, Stefan Wirtz, Christoph Daniel, Annegret Reinhold, Swen Engelmann, Stefanie Kliche, Christian Bogdan, Kasper Hoebe, Jochen Mattner

Research output: Contribution to journalArticle

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-76ace/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-76ace/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-76ace/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.

Original languageUndefined/Unknown
JournalPaediatrics and Child Health, East Africa
DOIs
Publication statusPublished - 1 Sept 2016

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