The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR signaling thresholds

Carter, Jennifer D.; Neel, Benjamin G.; Lorenz, Ulrike

doi:10.1093/intimm/11.12.1999

Cited by 74 publications

(94 citation statements)

References 49 publications

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“…We had previously reported that SHP-1 plays a role during thymic T cell development by influencing the TCR signal strength (30). 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).…”

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

confidence: 55%

“…(BALB/c:me/ϩ), (BALB/c:ϩ/ϩ:DO11.10 TCR-Tg ϩ ), and (BALB/c:me/ ϩ:DO11.10 TCR-Tg ϩ ) mice (31) were bred in our colony to generate the various genotypes. Genotyping for all mice was performed as described (31).…”

Section: Micementioning

confidence: 99%

“…Genotyping for all mice was performed as described (31). Unless otherwise noted, 15-to 19-day-old mice were used throughout the study.…”

Section: Micementioning

confidence: 99%

“…These assays were performed as described previously (31). Briefly, SHP-1 was immunoprecipitated from lysates of the indicated numbers of purified CD4 ϩ CD25 ϩ or CD4 ϩ CD25 Ϫ T cells using 2 g of rabbit anti-SHP-1 Abs (Santa Cruz Biotechnology) followed by immunoblotting for SHP-1 with monoclonal anti-SHP-1 (clone 1SH01; NeoMarkers) at 1.35 g/ml.…”

Section: Immunoprecipitation and Immunoblottingmentioning

confidence: 99%

“…The role of SHP-1 in regulating thymic T cell selection is best revealed when the me/me genotype is crossed onto a TCR-Tg background (31)(32)(33)(34). Therefore, we examined mice expressing the DO11.10 Tg TCR in a me/me background (31) for the presence of CD4 ϩ CD25 ϩ T reg cells.…”

Section: Do1110 Tcr-tg Me/me Mice Are Enriched For Cd4 ϩ Cd25 ϩ T Cementioning

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

confidence: 55%

Section: Micementioning

confidence: 99%

“…Genotyping for all mice was performed as described (31). Unless otherwise noted, 15-to 19-day-old mice were used throughout the study.…”

Section: Micementioning

confidence: 99%

Section: Immunoprecipitation and Immunoblottingmentioning

confidence: 99%

Section: Do1110 Tcr-tg Me/me Mice Are Enriched For Cd4 ϩ Cd25 ϩ T Cementioning

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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Requirement for CD28 co-stimulation is lower in SHP-1-deficient T cells

et al. 2001

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This study provides biochemical and functional evidence pertaining to the role of the intracellular protein tyrosine phosphatase, SHP‐1, in influencing thresholds for TCR activation. Although the loss of SHP‐1 in thymocytes from motheaten mice had minimal effects on the initial rise of cytosolic Ca2+ concentration following TCR triggering, the post‐stimulation equilibrium levelsof Ca2+ were consistently elevated. In keeping with a SHP‐1 effect on PLCγ function, IP3 generation was increased in SHP‐1 deficient thymocytes. Importantly, we demonstrate that loss of SHP‐1 results in a relaxation of the normally stringent co‐stimulatory requirements for IL‐2 production. SHP‐1 deficient single‐positive CD4+ thymocytes revealed a significantly enhanced capacity to produce IL‐2 in response to anti‐CD3 stimulation alone. In contrast, the simultaneous triggering of CD3 and CD28 was required for equivalent IL‐2 production in control single‐positive CD4+ thymocytes. Furthermore, SHP‐1 deficient thymocytes generated an increased and prolonged proliferative response to anti‐CD3 stimulation alone. In addition, the simultaneous triggering of CD28 and CD3 resulted in equivalent proliferative responses in SHP‐1‐deficient and control thymocytes, suggesting that a strong co‐stimulatory signal is able to override the effect of SHP‐1 loss on TCR hyperresponsiveness. Collectively, these results suggest that SHP‐1, rather than acting directly on TCR signaling, may indirectly raise thresholds for TCR triggering by modulating co‐stimulatory signals.

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Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection

et al. 2016

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SHP1 is a tyrosine phosphatase critical to proximal regulation of TCR signaling. Here, analysis of CD4-Cre SHP1fl/fl conditional knockout thymocytes using CD53, TCRβ, CD69, CD4 and CD8α expression demonstrates the importance of SHP1 in the survival of post selection (CD53+), single-positive thymocytes. Using Ca2+ flux to assess the intensity of TCR signaling demonstrated that SHP1 dampens the signal strength of these same mature, post-selection thymocytes. Consistent with its dampening effect, TCR signal strength was also probed functionally using peptides that can mediate selection of the OT-I TCR, to reveal increased negative selection mediated by lower-affinity ligand in the absence of SHP1. Our data show that SHP1 is required for the survival of mature thymocytes and the generation of the functional T-cell repertoire, as its absence leads to a reduction in the numbers of CD4+ and CD8+ naïve T cells in the peripheral lymphoid compartments.

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The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR signaling thresholds

Cited by 74 publications

References 49 publications

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

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

Requirement for CD28 co-stimulation is lower in SHP-1-deficient T cells

Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection

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