Editors' ChoiceImmunology

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Sci. Signal.  01 Feb 2011:
Vol. 4, Issue 158, pp. ec31
DOI: 10.1126/scisignal.4158ec31

The presence of peptide-loaded major histocompatibility complex on an antigen-presenting cell results in the ligation of the T cell receptor (TCR) on T cells, which induces the activation of the tyrosine kinase Zap70 (ζ chain–associated protein kinase of 70 kD). In turn, Zap70 phosphorylates the adaptor proteins LAT (linker for activation of T cells) and SLP-76 (SH2 domain–containing leukocyte phosphoprotein of 76 kD), which triggers the assembly of molecular complexes and downstream signaling. Compared with antigen-experienced T cells, naïve T cells have slower and weaker responses to ligation of the TCR, but the reason for these different responses has not been clear. Adachi and Davis found increased phosphorylation and activation of extracellular signal–regulated kinase (ERK) in naïve compared with antigen-experienced human T cells in which CD3 and CD28 were cross-linked with antibodies to ligate the TCR. SLP-76 is required for activation of ERK signaling downstream of TCR ligation, and phosphorylation of SLP76 was enhanced in naïve T cells. Furthermore, ERK signaling suppressed Ca2+ influx in naïve T cells and decreased the association of SLP76 with LAT, which the authors suggested might be due to increased degradation of the LAT signalosome. In contrast, phosphorylation and activation of p38 were higher in stimulated antigen-experienced than in naïve T cells. The scaffold protein hDlg (human Discs large) can enable phosphorylation and activation of p38 by Zap70 and the tyrosine kinase Lck, and TCR ligation induced the association of hDlg with phosphorylated p38 in antigen-experienced cells but not in naïve cells. Thus, activation of the TCR elicits different signaling pathways in naïve and experienced human T cells, which could serve as the basis for therapies that preferentially boost the response of naïve T cells when an enhanced immune response is needed (such as during infection) or dampen that of experienced T cells (which would be desirable in autoimmune diseases).

K. Adachi, M. M. Davis, T-cell receptor ligation induces distinct signaling pathways in naïve vs. antigen-experienced T cells. Proc. Natl. Acad. Sci. U.S.A. 108, 1549–1554 (2011). [Abstract] [Full Text]

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