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*
Department of Medicine, University of Wales College of Medicine, Cardiff, Wales, United Kingdom;
Immunology Unit, Glaxo-Wellcome Medicines Research Centre, Stevenage, Hertfordshire, United Kingdom; and
Department of Immunology, University Hospital Utrecht, Utrecht, The Netherlands
The intracellular Src homology 2 (SH2) domain-containing protein
tyrosine phosphatase (SHP-1) is a negative regulator of cell signaling
and contributes to the establishment of TCR signaling thresholds in
both developing and mature T lymphocytes. Although there is much
functional data implicating SHP-1 as a regulator of TCR signaling, the
molecular basis for SHP-1 activation in T lymphocytes is poorly
defined. A modification of the yeast two-hybrid system was employed to
identify in T cells phosphotyrosine-containing proteins capable of
binding the SH2 domains of SHP-1. From this yeast tri-hybrid screen,
the p85
subunit of phosphatidylinositol 3-kinase and the
immunoreceptor tyrosine-based inhibitory motif-containing receptors,
leukocyte-associated Ig-like receptor-1 (LAIR-1) and programmed death-1
(PD-1), were identified. Coimmunoprecipitation studies demonstrated
that the exclusive phosphotyrosine-containing protein associated with
SHP-1 in Jurkat T cells under physiological conditions is LAIR-1.
Significantly, this interaction is constitutive and was detected only
in the membrane-enriched fraction of cell lysates. Ligand engagement of
the SH2 domains of SHP-1 is a prerequisite to activation of the enzyme,
and, consistent with an association with LAIR-1, SHP-1 was found to be
constitutively active in unstimulated Jurkat T cells. Importantly, a
constitutive interaction between LAIR-1 and SHP-1 was also detected in
human primary T cells. These results illustrate the sustained
recruitment and activation of SHP-1 at the plasma membrane of resting
human T cells by an inhibitory receptor. We propose that this mechanism
may exert a constitutive negative regulatory role upon T cell
signaling.
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