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

Martinez, Ryan; Morris, Anna B.; Neeld, Dennis; Evavold, Brian D.

doi:10.1002/eji.201646475

Cited by 33 publications

(51 citation statements)

References 39 publications

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“…To test this possibility, we crossed mice carrying floxed alleles of Ptpn6 (Shp1) 19 with mice that express the Cre recombinase under the control of the distal promoter of Lck 17 . The distal Lck promoter drives Cre expression at late stages of T cell development, allowing TCR-dependent selection to occur under conditions of SHP-1 sufficiency 12,16,18,20 . We confirmed that SHP-1 was deleted in peripheral CD4+ (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This was done using the motheaten ( me/me ) mouse model, in which all hematopoietic cells lack SHP-1 due to a splicing mutation 14 , as well as cell lines expressing dominant negative mutant forms of SHP-1 12 . However, one recent study 15 , using conditional T cell deletion of SHP-1 via CD4-Cre, challenged the role of SHP-1 in regulating T cell development, while another report using the same mouse model confirmed the role of SHP-1 during T cell development 16 . Here, we generated a conditional knockout mouse model wherein SHP-1 deletion is driven by the distal Lck promoter 17 , resulting in abrogation of SHP-1 expression in post-selection thymocytes.…”

Section: Introductionmentioning

confidence: 99%

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

Mercadante

Lorenz

2017

The Journal of Immunology

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The balance between activation of T cells and their suppression by regulatory T cells (Treg) is dysregulated in autoimmune diseases and cancer. Autoimmune diseases feature T cells that are resistant to suppression by Tregs, whereas in cancer, T cells are unable to mount anti-tumor responses due to the Treg-enriched suppressive microenvironment. Here, we observe that loss of the tyrosine phosphatase SHP-1, a negative regulator of T cell receptor (TCR) signaling, renders naïve CD4+ and CD8+ T cells resistant to Treg-mediated suppression in a T cell-intrinsic manner. At the intracellular level, SHP-1 controlled the extent of Akt activation, which has been linked to the induction of T cell resistance to Treg suppression. Finally, under conditions of homeostatic expansion, SHP-1-deficient CD4+ T cells resisted Treg suppression in vivo. Collectively, these data establish SHP-1 as a critical player in setting the threshold downstream of TCR signaling and identify a novel function of SHP-1 as a regulator of T cell susceptibility to Treg-mediated suppression in vitro and in vivo. Thus, SHP-1 could represent a potential novel immunotherapeutic target to modulate susceptibility of T cells to Treg suppression.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Mercadante

Lorenz

2017

The Journal of Immunology

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“…The phenotype of Ptpn6 −/− mice does not resemble that of Themis −/− mice as might have been predicted by Model 1 [24, 25]. In contrast to Themis −/− mice, positive selection is not markedly impaired in Ptpn6 −/− mice [24], although the survival of post-selection SP thymocytes is reduced, possibly due to enhanced negative selection [25].…”

Section: Examining the Evidence For Model 1 And Modelmentioning

confidence: 99%

“…In contrast to Themis −/− mice, positive selection is not markedly impaired in Ptpn6 −/− mice [24], although the survival of post-selection SP thymocytes is reduced, possibly due to enhanced negative selection [25]. In Themis −/− mice, a defect in thymocyte maturation is observed at the first stage of positive selection (TCR int CD69 int ) [1, 3] whereas Ptpn6 −/− mice do not exhibit a developmental defect until the later TCR hi CD69 hi post-selection stage [25]. Also, CD4 SP thymocyte and T cell numbers are unaffected or only slightly reduced in Ptpn6 −/− mice [24, 25] but are strongly diminished in Themis −/− mice [1–5].…”

Section: Examining the Evidence For Model 1 And Modelmentioning

confidence: 99%

“…In Themis −/− mice, a defect in thymocyte maturation is observed at the first stage of positive selection (TCR int CD69 int ) [1, 3] whereas Ptpn6 −/− mice do not exhibit a developmental defect until the later TCR hi CD69 hi post-selection stage [25]. Also, CD4 SP thymocyte and T cell numbers are unaffected or only slightly reduced in Ptpn6 −/− mice [24, 25] but are strongly diminished in Themis −/− mice [1–5]. The proponents of Model 1 have proposed that positive regulation of both SHP-1 and the closely related but widely expressed SH2 PTP, SHP-2 by THEMIS could explain the milder phenotype of Ptpn6 −/− mice compared to Themis −/− mice if SHP-1 and SHP-2 are functionally redundant, and predicted that the phenotype of thymocytes lacking both SHP-1 and SHP-2 should phenocopy that of Themis −/− thymocytes [15].…”

Section: Examining the Evidence For Model 1 And Modelmentioning

confidence: 99%

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THEMIS: Two Models, Different Thresholds

Choi

Cornall

Lesourne

et al. 2017

Trends in Immunology

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THEMIS, a recently identified T-lineage restricted protein, is the founding member of a large metazoan protein family. Gene inactivation studies have revealed a critical requirement for THEMIS during thymocyte positive selection, implicating THEMIS in signaling downstream of the T cell antigen receptor (TCR); but the mechanistic underpinnings of THEMIS’ function have remained elusive. A previous model posited that THEMIS prevents thymocytes from inappropriately crossing the positive/negative selection threshold by dampening TCR signaling. However, new data suggest an alternative model where THEMIS enhances TCR signaling, enabling thymocytes to reach the threshold for positive selection avoiding death by neglect. We review the data supporting each model and conclude that the preponderance of evidence favors an enhancing function for THEMIS in TCR signaling.

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SHP1‐ing thymic selection

et al. 2016

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The development of conventional T cells in the thymus is highly dependent on parsing small differences in TCR affinity for self MHC-peptide, and responding with the induction of cell-survival and differentiation signals (positive selection) or with activationinduced cell death (negative selection). Regulation of TCR signal strength is important in defining the boundary between positive and negative selection [1,2]. TCR ligation leads to phosphorylation of ITAMs on the CD3 complex by Lck kinase, resulting in recruitment and tyrosine phosphorylation of the tyrosine kinase ZAP70. Activated ZAP70 can then phosphorylate the scaffold proteins LAT and SLP76, resulting in activation of multiple downstream signalling pathways [2]. As the initiation and maintenance of TCR signalling pathways are critically dependent on protein Correspondence: Dr. Nicholas R.J. Gascoigne e-mail: micnrjg@nus.edu.sg tyrosine phosphorylation, counteraction by tyrosine phosphatases plays a major role in negative regulation of TCR signal strength. SHP1 (Src homology region 2 domain-containing phosphatase-1), or PTPN6, is a tyrosine phosphatase that has been suggested to control TCR signalling in the thymus and periphery [3]. However, the precise role of SHP1 in thymic development has been the subject of controversy, with reports suggesting either a major [4] Early studies of SHP1-deficient "motheaten" mice showed that this phosphatase is important for TCR signalling and specifically, in setting the threshold for positive and negative selection [4,[7][8][9]. However, the complete loss of SHP1 expression leads to systemic inflammation in SHP1-deficient mice, influencing thymocyte differentiation, and calling into question the validity of the interpretation of data from these mice. A recent study looked at the role of SHP1 in thymic differentiation using CD4-Cre-mediated conditional knockout of SHP1 only in the T-cell lineage, prior to positive selection. They did not see any defect in positive or negative selection [5]. The work of Martinez et al. re-examines this question in mice of the same genotype, but performing a more in-depth analysis of thymocyte development [6].Thymocyte development proceeds along a set of well-defined developmental stages (Fig. 1A) after stimulation with weak peptide ligands, suggesting that SHP1 acts to set the positive versus negative selection threshold by dampening TCR signal strength [6]. This enhanced TCR signalling leading to negative selection in response to relatively weak peptide MHC ligands is similar to the phenotype of mice that are deficient for Themis [11]. Themis is a protein that is important at the positive selection checkpoint [12][13][14][15][16], which interacts with SHP1 [11,17,18]. Both proteins, Themis and SHP1, bind to the adapter protein GRB2, allowing their recruitment to the LAT signalosome [17,19]. Themisdeficient thymocytes show reduced levels of SHP1 tyrosine phosphorylation [11], suggesting that Themis controls SHP1 phosphatase activity in thymocytes. Analysis of themis-deficiency in mou...

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

Cited by 33 publications

References 39 publications

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

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

THEMIS: Two Models, Different Thresholds

SHP1‐ing thymic selection

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