The Role of the LAT–PLC-γ1 Interaction in T Regulatory Cell Function

Chuck, Mariana; Zhu, Minghua; Shen, Shudan; Zhang, Weiguo

doi:10.4049/jimmunol.0902876

Cited by 54 publications

(72 citation statements)

References 47 publications

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“…We used a qRT-PCR array for screening genes functionally associated with immune tolerance and anergy (data not shown). Notably, among other discrete changes, we observed a consistent altered expression of Lat, a gene that encodes a tyrosine phosphorylated transmembrane adaptor protein whose expression is associated with the suppressive activity of T reg cells (37,38). Recent findings showed that inhibition of LAT in mice leads to impaired immune tolerance due to diminished suppressive activity of T reg cells (37).…”

Section: Cd25mentioning

confidence: 72%

“…þ T reg cells (37), highlighting the importance of LAT as an inhibitory checkpoint during immune cell homeostasis. In agreement, our findings show that T reg cells from mice bearing Gal1 KD tumors express lower LAT levels and have reduced suppressive activity.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, among other discrete changes, we observed a consistent altered expression of Lat, a gene that encodes a tyrosine phosphorylated transmembrane adaptor protein whose expression is associated with the suppressive activity of T reg cells (37,38). Recent findings showed that inhibition of LAT in mice leads to impaired immune tolerance due to diminished suppressive activity of T reg cells (37). Consistent with this observation, we observed substantial downregulation of LAT expression in CD4 þ T cells isolated from pulmonary metastasis, primary tumor, and spleen of mice bearing 4T1 Gal1 KD tumors (Fig.…”

Section: Cd25mentioning

confidence: 90%

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Targeting Galectin-1 Overcomes Breast Cancer-Associated Immunosuppression and Prevents Metastatic Disease

et al. 2013

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Galectin-1 (Gal1), an evolutionarily conserved glycan-binding protein, contributes to the creation of an immunosuppressed microenvironment at sites of tumor growth. In spite of considerable progress in elucidating its role in tumor-immune escape, the mechanisms underlying the inhibitory functions of Gal1 remain obscure. Here, we investigated the contribution of tumor Gal1 to tumor growth, metastasis, and immunosuppression in breast cancer. We found that the frequency of Gal1 þ cells in human breast cancer biopsies correlated positively with tumor grade, while specimens from patients with benign hyperplasia showed negative or limited Gal1 staining. To examine the pathophysiologic relevance of Gal1 in breast cancer, we used the metastatic mouse mammary tumor 4T1, which expresses and secretes substantial amounts of Gal1. Silencing Gal1 expression in this model induced a marked reduction in both tumor growth and the number of lung metastases. This effect was abrogated when mice were inoculated with wild-type 4T1 tumor cells in their contralateral flank, suggesting involvement of a systemic modulation of the immune response. Gal1 attenuation in 4T1 cells also reduced the frequency of CD4cells within the tumor, draining lymph nodes, spleen, and lung metastases. Further, it abrogated the immunosuppressive function of T reg cells and selectively lowered the expression of the T-cell regulatory molecule LAT (linker for activation of T cells) on these cells, disarming their suppressive activity. Taken together, our results offer a preclinical proof of concept that therapeutic targeting of Gal1 can overcome breast cancer-associated immunosuppression and can prevent metastatic disease. Cancer Res; 73(3); 1107-17. Ó2012 AACR.

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Section: Cd25mentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Cd25mentioning

confidence: 90%

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Targeting Galectin-1 Overcomes Breast Cancer-Associated Immunosuppression and Prevents Metastatic Disease

et al. 2013

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“…In contrast, Akt activation was not affected by Themis1 deficiency. Together, these results show that Themis1 interacts more efficiently with Vav1-W63 variant and is required to stabilize its recruitment to the transmembrane adaptor LAT to fully promote the activation of Erk kinases that are likely necessary for the suppressive functions of Tregs (29)(30)(31).…”

Section: Vav1 Variants Impact On Themis1/vav1 Interplay and Affect Tcmentioning

confidence: 79%

“…These data are consistent with previous reports showing the critical role of the integrity of LAT signaling platform as well as Erk activation for the Treg suppressive function and the Th1/Th2 polarization (29-31, 43, 44). Indeed, the disruption of LAT/ PLC-g signalosome assembly reduces Erk and Ca 2+ activation (29,30) and despite normal Foxp3 expression, LAT-or PLCg-deficient Tregs are ineffective in controlling the proliferation of effector T cells (29)(30)(31). In addition, sustained Erk activity and calcium signaling impact on the Th1/Th2 polarization, promoting Th1 differentiation (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

An Epistatic Interaction between Themis1 and Vav1 Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development

Pedros

Gaud

Bernard

et al. 2015

The Journal of Immunology

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The development of inflammatory diseases depends on complex interactions between several genes and various environmental factors. Discovering new genetic risk factors and understanding the mechanisms whereby they influence disease development is of paramount importance. We previously reported that deficiency in Themis1, a new actor of TCR signaling, impairs regulatory T cell (Treg) function and predisposes Brown–Norway (BN) rats to spontaneous inflammatory bowel disease (IBD). In this study, we reveal that the epistasis between Themis1 and Vav1 controls the occurrence of these phenotypes. Indeed, by contrast with BN rats, Themis1 deficiency in Lewis rats neither impairs Treg suppressive functions nor induces pathological manifestations. By using congenic lines on the BN genomic background, we show that the impact of Themis1 deficiency on Treg suppressive functions depends on a 117-kb interval coding for a R63W polymorphism that impacts Vav1 expression and functions. Indeed, the introduction of a 117-kb interval containing the Lewis Vav1-R63 variant restores Treg function and protects Themis1-deficient BN rats from spontaneous IBD development. We further show that Themis1 binds more efficiently to the BN Vav1-W63 variant and is required to stabilize its recruitment to the transmembrane adaptor LAT and to fully promote the activation of Erk kinases. Together, these results highlight the importance of the signaling pathway involving epistasis between Themis1 and Vav1 in the control of Treg suppressive function and susceptibility to IBD development.

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TCR signalling network organization at the immunological synapses of murine regulatory T cells

et al. 2017

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Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in www.eji-journal.euThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 2Marco van Ham et al. Eur. J. Immunol. 2017. 0: 1-16 in Treg cells, thereby, seems to be differentially organized as in Tconv cells: Treg cells show reduced Ca 2+ flux and ERK1/2 phosphorylation upon TCR stimulation [6][7][8], and downstream signalling molecules such as Lck, LAT and PLCγ1 are essential for Treg cell suppressive capacity [9,10]. In this line, a novel TCRmediated ADAP/integrin-independent PLCγ1 activation pathway was described to be required for suppression of Tconv cells by Treg cells [11]. Furthermore, Treg cells exhibit reduced S473 phosphorylation of Akt which seems a prerequisite for suppression [12]. Although the enzymatic activity of the tyrosine kinase ZAP70 seems to be dispensable for the suppressive phenotype of Foxp3 + Treg cells [13], a single mutation within the SH2-domain of ZAP70 leads to impaired suppressive activities, which indicated its importance at the immunological synapse (IS) [14]. Finally, it has only recently been recognized that the recruitment of TCR signalling components into the IS is differentially organized in Treg cells and Tconv cells. The protein kinase PKCθ is recruited to the IS in Tconv cells, in Treg cells, however, this kinase was found to be sequestered away from the IS, but still of importance to control suppression [15]. The spatial recruitment of signalling components during IS formation critically depends on cytoskeleton dynamics, which in turn is controlled by TCR activation and subsequent phosphorylation of proteins regulating cytoskeleton reorganization [5]. As part of these processes the microtubule-organizing centre (MTOC) is rapidly translocated in proximity to the IS. MTOC repositioning depends on LAT, ZAP70 and SLP76 [16] and is regulated by a cascade of distinct isoforms of the family of novel protein kinase C (nPKC) [17]. The MTOC serves as a platform to coordinate molecular movements from and to the IS through the support of microtubule (MT) motors [18]. For instance, TCR microclusters move along MTs towards the centre of the IS in a dynein-dependent manner [19], and hindrance of MTOC polarization, molecular transport and cytoskeleton dynamics prevent proper propagation of TCR signals [20].It is now tempting to speculate that the localization of signalling modules within the IS may be instrumental for the formation of a Treg cell-specific IS and the suppressive phenotype of Treg cells. At this moment, however,...

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The Role of the LAT–PLC-γ1 Interaction in T Regulatory Cell Function

Cited by 54 publications

References 47 publications

Targeting Galectin-1 Overcomes Breast Cancer-Associated Immunosuppression and Prevents Metastatic Disease

Targeting Galectin-1 Overcomes Breast Cancer-Associated Immunosuppression and Prevents Metastatic Disease

An Epistatic Interaction between Themis1 and Vav1 Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development

TCR signalling network organization at the immunological synapses of murine regulatory T cells

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