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TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways

Abstract

Functional discrimination between structurally similar self and foreign antigens is a main attribute of adaptive immunity. Here we describe two feedback mechanisms in T lymphocytes that together sharpen and amplify initial signaling differences related to the quality of T cell receptor (TCR) engagement. Weakly binding ligands predominantly trigger a negative feedback loop leading to rapid recruitment of the tyrosine phosphatase SHP-1, followed by receptor desensitization through inactivation of Lck kinase. In contrast, strongly binding ligands efficiently activate a positive feedback circuit involving Lck modification by ERK, preventing SHP-1 recruitment and allowing the long-lasting signaling necessary for gene activation. The characteristics of these pathways suggest that they constitute an important part of the mechanism allowing T cells to discriminate between self and foreign ligands.

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Figure 1: Involvement of SHP-1 in inhibition induced by TCR antagonists.
Figure 2: ERK modification of Lck interferes with SHP-1 binding.
Figure 3: Role of ERK in SHP-1 binding and agonist-induced proximal TCR signaling in human T cells.
Figure 4: Temporal pattern of ERK activation and SHP-1 recruitment in T cells exposed to partial agonist.

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Acknowledgements

We thank J. Bolen for antibodies and Gst-Lck; A. Veillette for Lck cDNAs; T. Yi for the cDNA for SHP-1 and SHP-1 (C453S); A. Rinker for preparation of the Y564F mutant SHP-1 and S59A and S59E mutant Lck cDNAs; and E. Long, L. Samelson, P. Schwartzberg, M. Lenardo, J. Delon, M. Meier-Schellersheim and G. Bonnet for comments on the manuscript.

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Correspondence to Ronald N. Germain.

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Štefanová, I., Hemmer, B., Vergelli, M. et al. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol 4, 248–254 (2003). https://doi.org/10.1038/ni895

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