Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signalling

Zhang, Jinyi; Somani, Ally Khan; Siminovitch, Katherine A.

doi:10.1006/smim.2000.0223

Cited by 329 publications

(303 citation statements)

References 185 publications

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“…In accordance with recent reports (26,27), the thymus of B6 dnSHP-1 mice showed a normal size and subset distribution (Table I and data not shown). Splenic CD4 and CD8 T cells included equal populations of CD62L low and CD44 high (memory) cells in B6 and B6 dnSHP-1 transgenic mice (data not shown).…”

Section: T Cell and Nk Cell Development In Dnshp-1 Transgenic Micesupporting

confidence: 93%

Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

Lowin-Kropf

Kunz

Beermann³

et al. 2000

The Journal of Immunology

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NK cell function is negatively regulated by MHC class I-specific inhibitory receptors. Transduction of the inhibitory signal involves protein tyrosine phosphatases such as SHP-1 (SH2-containing protein tyrosine phosphatase-1). To investigate the role of SHP-1 for NK cell development and function, we generated mice expressing a catalytically inactive, dominant-negative mutant of SHP-1 (dnSHP-1). In this paper we show that expression of dnSHP-1 does not affect the generation of NK cells even though MHC receptor-mediated inhibition is partially impaired. Despite this defect, these NK cells do not kill syngeneic, normal target cells. In fact dnSHP-1-expressing NK cells are hyporesponsive toward MHC-deficient target cells, suggesting that non-MHC-specific NK cell activation is significantly reduced. In contrast, these NK cells mediate Ab-dependent cell-mediated cytotoxicity and prevent the engraftment with β2-microglobulin-deficient bone marrow cells. A similar NK cell phenotype is observed in viable motheaten (mev) mice, which show reduced SHP-1 activity due to a mutation in the Shp-1 gene. In addition, NK cells in both mouse strains show a tendency to express more inhibitory MHC-specific Ly49 receptors. Our results demonstrate the importance of SHP-1 for the generation of functional NK cells, which are able to react efficiently to the absence of MHC class I molecules from normal target cells. Therefore, SHP-1 may play an as-yet-unrecognized role in some NK cell activation pathways. Alternatively, a reduced capacity to transduce SHP-1-dependent inhibitory signals during NK cell development may be compensated by the down-modulation of NK cell triggering pathways.

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Section: T Cell and Nk Cell Development In Dnshp-1 Transgenic Micesupporting

confidence: 93%

Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

Lowin-Kropf

Kunz

Beermann³

et al. 2000

The Journal of Immunology

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“…Using a transgenic TCR system, bred into the motheaten background, we observed that SHP-1 is involved in setting the thresholds for positive and negative selection (31). Other reports have also noted similar effects of SHP-1 on thymic selection (32)(33)(34). Taken together, these studies are consistent with a regulatory role for SHP-1 during T cell development.…”

Section: Deficiency Of the Src Homology Region 2 Domain-containing Phsupporting

confidence: 57%

“…This translates to SHP-1 setting thresholds for positive and negative selection during thymic T cell development (31)(32)(33)(34). The presence of high-affinity peptides during thymic selection has been shown to promote T reg cell development (11,12,14).…”

Section: Discussionmentioning

confidence: 99%

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Deficiency of the Src Homology Region 2 Domain-Containing Phosphatase 1 (SHP-1) Causes Enrichment of CD4+CD25+ Regulatory T Cells

Carter

Calabrese

Lorenz

2005

The Journal of Immunology

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A subpopulation of T cells, named regulatory T cells (Treg cells), has been shown to play a key role in tolerance and the prevention of autoimmunity. It is not known how changes in TCR signal strength during thymic T cell development affect the generation of a Treg population. In this study, we took two different strategies to modulate the TCR signal strength: an intrinsic approach, where signaling was enhanced by the loss of a negative regulator, and an extrinsic approach, where signaling strength was altered through variations in the concentrations of the selecting peptide. The tyrosine phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1) is a known negative regulator of TCR-mediated signaling. motheaten mice, lacking expression of SHP-1, showed a 2- to 3-fold increase in the percentage of CD4+CD25+ Treg cells within the CD4+ T cells. Similarly, the percentage of Treg cells was heightened in fetal thymic organ cultures (FTOCs) derived from motheaten mice compared with wild-type FTOCs, thus establishing the thymic origin of these Treg cells. Using FTOCs derived from DO11.10 TCR transgenic mice, we demonstrated that exposure to increasing concentrations of the cognate OVA peptide favored the appearance of Treg cells. Our data suggest that the development of CD4+CD25+ Treg cells is intrinsically different from non-Treg cells and that Treg cells are selectively enriched under conditions of enhanced negative selection. Our data also reveal a key role for the SHP-1-mediated regulation of TCR signal strength in influencing the ratio of Treg vs non-Treg cells.

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“…This cannot only be a result of a selective disadvantage provided by what we now recognize as autoimmune diseases, although those conditions -such as SLE -that appear early in the reproductive years may have played some role. Rather, it is the avoidance of serious, early autoimmune reactions, as are seen in certain mouse models such as the TGF-b knockout [6] or the spontaneous motheaten (SHP-1) mutations [7], that would ensure that the maintenance of self tolerance is highly important to the survival of the species.…”

Section: Distinguishing Self Versus Non-selfmentioning

confidence: 99%

Do autoantigens define autoimmunity or vice versa?

Eisenberg

2005

Eur J Immunol

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The basic function of the adaptive immune system is to distinguish self from foreign. The failure of self tolerance can result in autoimmunity, which comes in many forms but still targets a limited selection of the total available autologous determinants. This selectivity must reflect the underlying mechanisms of the autoimmune reaction, as well as the particular features of the autoantigens that are targeted. Here I discuss the overall paradigm of autoimmunity, and what kinds of mechanisms might play a role. It is likely that multiple different pathways are critical in various diseases, and even in a single condition.

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Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signalling

Cited by 329 publications

References 185 publications

Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

Deficiency of the Src Homology Region 2 Domain-Containing Phosphatase 1 (SHP-1) Causes Enrichment of CD4+CD25+ Regulatory T Cells

Do autoantigens define autoimmunity or vice versa?

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