Shp1 regulates T cell homeostasis by limiting IL-4 signals

Johnson, Dylan; Pao, Lily; Dhanji, Salim; Murakami, Kiichi; Ohashi, Pamela S.; Neel, Benjamin G.

doi:10.1084/jem.20122239

Cited by 85 publications

(125 citation statements)

References 75 publications

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“…Unlike other immune cells, such as B cells 30 , CD4 þ T cells 41 , regulatory T cells 42 , dendritic cells and neutrophils 43 , we show here that SHP-1-deficient NK cells are hyporesponsive and do not promote inflammation or autoimmunity. NK cells are, to our knowledge, the only cell type in which a lack of SHP-1 increases, rather than decreases, the activation threshold.…”

Section: Discussionmentioning

confidence: 50%

SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells

et al. 2014

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Natural killer (NK) cells are cytotoxic innate lymphoid cells that are involved in immune defense. NK cell reactivity is controlled in part by MHC class I recognition by inhibitory receptors, but the underlying molecular mechanisms remain undefined. Using a mouse model of conditional deletion in NK cells, we show here that the protein tyrosine phosphatase SHP-1 is essential for the inhibitory function of NK cell MHC class I receptors. In the absence of SHP-1, NK cells are hyporesponsive to tumour cells in vitro and their early Ca 2 þ signals are compromised. Mice without SHP-1 in NK cells are unable to reject MHC class I-deficient transplants and to control tumours in vivo. Thus, the inhibitory activity of SHP-1 is needed for setting the threshold of NK cell reactivity.

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Section: Discussionmentioning

confidence: 50%

SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells

et al. 2014

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“…This was challenged in a recent study using Cre recombinase gene under transcriptional control of elements of the Cd4 gene to induce conditional deletion of Shp-1. No obvious differences in positive or negative selection relative to wild-type cells were seen (66). However, as already suggested by the findings of Marquez et al (63), tuning mechanisms are likely to be 9:51 redundant and context-dependent rather than stereotypic.…”

Section: Cd5 Mediates Dynamic Tuningmentioning

confidence: 55%

Dynamic Tuning of Lymphocytes: Physiological Basis, Mechanisms, and Function

Grossman

Paul

2015

Annu. Rev. Immunol.

104

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Dynamic tuning of cellular responsiveness as a result of repeated stimuli improves the ability of cells to distinguish physiologically meaningful signals from each other and from noise. In particular, lymphocyte activation thresholds are subject to tuning, which contributes to maintaining tolerance to self-antigens and persisting foreign antigens, averting autoimmunity and immune pathogenesis, but allowing responses to strong, structured perturbations that are typically associated with acute infection. Such tuning is also implicated in conferring flexibility to positive selection in the thymus, in controlling the magnitude of the immune response, and in generating memory cells. Additional functional properties are dynamically and differentially tuned in parallel via subthreshold contact interactions between developing or mature lymphocytes and self-antigen-presenting cells. These interactions facilitate and regulate lymphocyte viability, maintain their functional integrity, and influence their responses to foreign antigens and accessory signals, qualitatively and quantitatively. Bidirectional tuning of T cells and antigen-presenting cells leads to the definition of homeostatic set points, thus maximizing clonal diversity.

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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].…”

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 regulates T cell homeostasis by limiting IL-4 signals

Abstract: Absence of the phosphatase Shp1 in T cells does not affect the TCR signaling threshold but results in IL-4 sensitivity and memory phenotype cells.

Cited by 85 publications

References 75 publications

SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells

SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells

Dynamic Tuning of Lymphocytes: Physiological Basis, Mechanisms, and Function

THEMIS: Two Models, Different Thresholds

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