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Fyn Regulates the Duration of TCR Engagement Needed for Commitment to Effector Function¹

Andrew Filby^*, Benedict Seddon, Joanna Kleczkowska^*, Robert Salmond^*, Peter Tomlinson^*, Michal Smida, Jonathan A. Lindquist, Burkhart Schraven and Rose Zamoyska^2,*

^* Division of Molecular Immunology and Division of Immune Cell Biology, Medical Research Council, National Institute for Medical Research, The Ridgeway, London, United Kingdom; and Institute of Immunology, Otto-von-Guericke University, Magdeburg, Germany

In naive T cells, engagement of the TCR with agonist peptide:MHC molecules leads to phosphorylation of key intracellular signaling intermediates within seconds and this peaks within minutes. However, the cell does not commit to proliferation and IL-2 cytokine production unless receptor contact is sustained for several hours. The biochemical basis for this transition to full activation may underlie how T cells receive survival signals while maintaining tolerance, and is currently not well understood. We show here that for CD8 T cells commitment to proliferation and cytokine production requires sustained activation of the Src family kinase Lck and is opposed by the action of Fyn. Thus, in the absence of Fyn, commitment to activation occurs more rapidly, the cells produce more IL-2, and undergo more rounds of division. Our data demonstrate a role for Fyn in modulating the response to Ag in primary T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Medical Research Council and Leukaemia Research Fund U.K.

² Address correspondence and reprint requests to Dr. Rose Zamoyska, Molecular Immunology, National Institute for Medical Research, The Ridgeway, London, U.K. E-mail address: rzamoys{at}nimr.mrc.ac.uk

³ Abbreviations used in this paper: pMHC, peptide MHC; SFK, Src family kinase; SHP-1, Src homology region 2 domain-containing phosphatase 1; Csk, C-terminal Src kinase; PM, plasma membrane; PAG, phosphoprotein associated with glycosphingolipid-enriched microdomains; dox, doxycycline; LN, lymph node; pdBU, phorbol 12,13-dibutyrate; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4,d]pyrimidine; PI, proliferation index; WT, wild type; MFI, mean fluorescence intensity; SMAC, supermolecular activation cluster.

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The JI 2007 179: 4297-4298. [Full Text]