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

Keishi Adachi^a,b Mark M. Davis^a,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

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

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 www.pnas.org/lookup/suppl/doi:10.1073/pnas.1017340108/-/DCSupplemental.

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

The Scaffolding Protein Synapse-Associated Protein 97 Is Required for Enhanced Signaling Through Isotype-Switched IgG Memory B Cell Receptors.

W. Liu, E. Chen, X. W. Zhao, Z. P. Wan, Y. R. Gao, A. Davey, E. Huang, L. Zhang, J. Crocetti, G. Sandoval, et al. (2012)
Science Signaling 5, ra54
 |  Abstract »  |  Full Text »  |  PDF »

Intrinsic Differences in the Initiation of B Cell Receptor Signaling Favor Responses of Human IgG+ Memory B Cells over IgM+ Naive B Cells.

A. M. Davey and S. K. Pierce (2012)
J. Immunol. 188, 3332-3341
 |  Abstract »  |  Full Text »  |  PDF »

Thymic negative selection is functional in NOD mice.

M. Mingueneau, W. Jiang, M. Feuerer, D. Mathis, and C. Benoist (2012)
J. Exp. Med. 209, 623-637
 |  Abstract »  |  Full Text »  |  PDF »

IL-2-Engineered nano-APC Effectively Activates Viral Antigen-Mediated T Cell Responses from Chronic Hepatitis B Virus-Infected Patients.

M. Liu, T. Miao, H. Zhu, A. L. J. Symonds, L. Li, A. Schurich, M. K. Maini, J. Zhang, P. T. F. Kennedy, S. Li, et al. (2012)
J. Immunol. 188, 1534-1543
 |  Abstract »  |  Full Text »  |  PDF »

Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function.

A. Zanin-Zhorov, J. Lin, J. Scher, S. Kumari, D. Blair, K. L. Hippen, B. R. Blazar, S. B. Abramson, J. J. Lafaille, and M. L. Dustin (2012)
PNAS 109, 1625-1630
 |  Abstract »  |  Full Text »  |  PDF »

Strength of TCR-Peptide/MHC Interactions and In Vivo T Cell Responses.

E. Corse, R. A. Gottschalk, and J. P. Allison (2011)
J. Immunol. 186, 5039-5045
 |  Abstract »  |  Full Text »  |  PDF »