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PNAS 108 (4): 1549-1554

Copyright © 2011 by the National Academy of Sciences.


T-cell receptor ligation induces distinct signaling pathways in naïve vs. antigen-experienced T cells

Keishi Adachia,b Mark M. Davisa,c,1

aThe Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; bDepartment of Parasitology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan; and cDepartment of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305

Contributed by Mark M. Davis, December 3, 2010 (sent for review May 10, 2010)

Abstract: Naïve T lymphocytes display weaker and slower responses than antigen-experienced cells for reasons that are not well understood. Here we show that T-cell receptor (TCR) stimulation induces distinct ERK and p38 phosphorylation patterns in naïve and antigen-experienced human T cells, and that these contribute to the differential responses shown by these cells. Specifically, TCR ligation triggers the activation of the ERK pathway in naïve cells. This phosphorylation of ERK attenuates subsequent calcium influx and accelerates the degradation of the signalsome. In contrast, anti-CD3 stimulation of experienced cells results in the phosphorylation of p38 via an association with Discs large (Dlg). Thus, there are distinct signaling pathways triggered by TCR ligation that impair signaling in naïve cells and facilitate it in antigen-experienced cells.

Key Words: T-cell signaling

Freely available online through the PNAS open access option.

Author contributions: K.A. and M.M.D. designed research; K.A. performed research; K.A. and M.M.D. analyzed data; and K.A. and M.M.D. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: mmdavis{at}

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