T Cells Deficient in the Tyrosine Phosphatase SHP-1 Resist Suppression by Regulatory T Cells

Mercadante, Emily; Lorenz, Ulrike

doi:10.4049/jimmunol.1602171

Cited by 28 publications

(31 citation statements)

References 58 publications

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“…Previous studies have also demonstrated an effect of Shp1 loss in T lymphocytes. Ptpn6 -deficient CD4 + and CD8 + T cells exhibit increased proliferation ( 20 , 21 , 56 ) and are less sensitive to suppression by regulatory T cells ( 57 ). A recent genome-wide CRISPR screen in primary human CD4+ T cells identified PTPN6 as a negative regulator of T cell proliferation ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity

et al. 2020

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Shp1, encoded by the gene Ptpn6 , is a protein tyrosine phosphatase that transduces inhibitory signals downstream of immunoreceptors in many immune cell types. Blocking Shp1 activity represents an exciting potential immunotherapeutic strategy for the treatment of cancer, as Shp1 inhibition would be predicted to unleash both innate and adaptive immunity against tumor cells. Antibodies blocking the interaction between CD47 on tumor cells and SIRPα on macrophages enhance macrophage phagocytosis, show efficacy in preclinical tumor models, and are being evaluated in the clinic. Here we found that Shp1 bound to phosphorylated peptide sequences derived from SIRPα and transduced the anti-phagocytic signal, as Shp1 loss in mouse bone marrow-derived macrophages increased phagocytosis of tumor cells in vitro . We also generated a novel mouse model to evaluate the impact of global, inducible Ptpn6 deletion on anti-tumor immunity. We found that inducible Shp1 loss drove an inflammatory disease in mice that was phenotypically similar to that seen when Ptpn6 is knocked out from birth. This indicates that acute perturbation of Shp1 in vivo could drive hyperactivation of immune cells, which could be therapeutically beneficial, though at the risk of potential toxicity. In this model, we found that Shp1 loss led to robust anti-tumor immunity against two immune-rich syngeneic tumor models that are moderately inflamed though not responsive to checkpoint inhibitors, MC38 and E0771. Shp1 loss did not promote anti-tumor activity in the non-inflamed B16F10 model. The observed activity in MC38 and E0771 tumors was likely due to effects of both innate and adaptive immune cells. Following Shp1 deletion, we observed increases in intratumoral myeloid cells in both models, which was more striking in E0771 tumors. E0771 tumors also contained an increased ratio of effector to regulatory T cells following Shp1 loss. This was not observed for MC38 tumors, though we did find increased levels of IFNγ, a cytokine produced by effector T cells, in these tumors. Overall, our preclinical data suggested that targeting Shp1 may be an attractive therapeutic strategy for boosting the immune response to cancer via a mechanism involving both innate and adaptive leukocytes.

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Section: Discussionmentioning

confidence: 99%

Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity

et al. 2020

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“…We observed a similar and selective decrease of integrin β 7 in CD4 + and CD8 + T cells (Figure 1A). Full SHP-1 deficiency leading to profound changes in the phenotype and homeostasis of mature B cells (Pao et al, 2007) and naïve T cells (Martinez et al, 2016;Mercadante and Lorenz, 2017), we repeated the above experiments with heterozygous viable motheaten mice (+/me V , or SHP-1 +/-). Despite some residual SHP-1 activity, SHP1 +/-B and T cells displayed a selective reduction of α 4 , β 7 , and α 4 β 7 integrins while expressing normal levels of α L , β 1 , and β 2 (Figure 1B).…”

Section: Shp-1 Selectively Controls α 4 β 7 Expression In Lymphocytesmentioning

confidence: 99%

Selective augmentation of intestinal immunity by CD22-dependent SHP-1 control of β₇integrin expression

Brandl

Feng

et al. 2020

Preprint

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The regulation of integrin expression and function controls interactions of immune cells and targets their trafficking locally and systemically. We show here that the tyrosine phosphatase SHP-1 is required for lymphocyte surface expression of the intestinal immune response-associated integrin β 7 , but not for β 1 or β 2 integrins. Viable motheaten mice deficient for SHP-1 have less β 7 on T cells and lack β 7 on B cells. SHP-1 function is targeted in B cells by the B cell specific lectin CD22 (Siglec-2), suggesting a potential role for CD22 in β 7 expression. CD22-deficiency on B cells phenocopies the effects of SHP-1 haplodeficiency. Mechanistically, we show that SHP-1 suppresses β 7 endocytosis: internalization of β 7 but not β 1 integrin is accelerated in SHP-1 +/and CD22 -/-B cells. Moreover, mutations in CD22 cytoplasmic SHP1-binding ITIM sequences reduce α 4 β 7 comparably, and loss of CD22 lectin activity has an intermediate effect suggesting a model in which the CD22 ITIM sequences recruit SHP-1 to control β 7 expression. Integrin α 4 β 7 selectively contributes to cell interactions in intestinal immunity. Consistent with this, CD22 deficient and SHP-1 +/-B cells display reduced β 7 -dependent homing to gut associated Peyer's patches (PP); and CD22-deficiency impairs intestinal but not systemic antibody responses and delays clearance of the gut pathogen rotavirus. The results define a novel role for SHP-1 in the differential control of leukocyte integrins and an unexpected integrin β 7 -specific role for CD22-SHP-1 interplay in mucosal immunity. 1470 1887 3759 WT CD22 R130E

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“…In direct contrast, Martinez et al, also using a T cell specific conditional knockout mouse, showed that PTPN6 depletion lowers the threshold of TCR activation and causes an increase in thymic negative selection and impairs the T cell repertoire ( 127 ). Most recently, it has been reported that in an alternate conditional knockout model, in which PTPN6 is deleted in post-selection thymocytes, CD4 + T cells are hyper-responsive to TCR stimulation and are intrinsically more resistant to Treg suppression ( 128 ).…”

Section: Ptp Regulation Of Cd4 + T Cell Activity Imentioning

confidence: 99%

Protein Tyrosine Phosphatases: Regulators of CD4 T Cells in Inflammatory Bowel Disease

Pike

Tremblay

2018

Front. Immunol.

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Protein tyrosine phosphatases (PTPs) play a critical role in co-ordinating the signaling networks that maintain lymphocyte homeostasis and direct lymphocyte activation. By dephosphorylating tyrosine residues, PTPs have been shown to modulate enzyme activity and both mediate and disrupt protein-protein interactions. Through these molecular mechanisms, PTPs ultimately impact lymphocyte responses to environmental cues such as inflammatory cytokines and chemokines, as well as antigenic stimulation. Mouse models of acute and chronic intestinal inflammation have been shown to be exacerbated in the absence of PTPs such as PTPN2 and PTPN22. This increase in disease severity is due in part to hyper-activation of lymphocytes in the absence of PTP activity. In accordance, human PTPs have been linked to intestinal inflammation. Genome wide association studies (GWAS) identified several PTPs within risk loci for inflammatory bowel disease (IBD). Therapeutically targeting PTP substrates and their associated signaling pathways, such as those implicated in CD4+ T cell responses, has demonstrated clinical efficacy. The current review focuses on the role of PTPs in controlling CD4+ T cell activity in the intestinal mucosa and how disruption of PTP activity in CD4+ T cells can contribute to intestinal inflammation.

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T Cells Deficient in the Tyrosine Phosphatase SHP-1 Resist Suppression by Regulatory T Cells

Cited by 28 publications

References 58 publications

Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity

Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity

Selective augmentation of intestinal immunity by CD22-dependent SHP-1 control of β₇integrin expression

Protein Tyrosine Phosphatases: Regulators of CD4 T Cells in Inflammatory Bowel Disease

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T Cells Deficient in the Tyrosine Phosphatase SHP-1 Resist Suppression by Regulatory T Cells

Cited by 28 publications

References 58 publications

Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity

Shp1 Loss Enhances Macrophage Effector Function and Promotes Anti-Tumor Immunity

Selective augmentation of intestinal immunity by CD22-dependent SHP-1 control of β7integrin expression

Protein Tyrosine Phosphatases: Regulators of CD4 T Cells in Inflammatory Bowel Disease

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Selective augmentation of intestinal immunity by CD22-dependent SHP-1 control of β₇integrin expression