Regulation of growth and survival of activated T cells by cell‐transducing inhibitors of Ras

Malik, Nasser; Gilroy, Derek W.; Kabouridis, Panagiotis S.

doi:10.1016/j.febslet.2008.11.042

Cited by 4 publications

(4 citation statements)

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“…9–14 The magnitude and duration of ERK activation appears to modulate T cell function. Overexpression of RAS or RAF can enhance T cell activation and proliferation and conversely inhibition of RAS blocks T cell activation (10,15,16). This pathway is also important in various T cell functions including the differentiation of T cell subtypes, cytokine signaling, chemotaxis and survival (17,18).…”

Section: Introductionmentioning

confidence: 99%

Paradoxical Activation of T Cells via Augmented ERK Signaling Mediated by a RAF Inhibitor

Callahan

Masters

Pratilas

et al. 2014

Cancer Immunology Research

105

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RAF inhibitors selectively block ERK signaling in BRAF-mutant melanomas and have defined a genotype-guided approach to care for this disease. RAF inhibitors have the opposite effect in BRAF wild-type tumor cells, where they cause hyperactivation of ERK signaling. Here, we predict that RAF inhibitors can enhance T cell activation, based upon the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells. To test this hypothesis, we have evaluated the effects of the RAF inhibitor BMS908662 on T cell activation and signaling in vitro and in vivo. We observe that T cell activation is enhanced in a concentration-dependent manner and that this effect corresponds with increased ERK signaling, consistent with paradoxical activation of the pathway. Furthermore, we find that the combination of BMS908662 with CTLA-4 blockade in vivo potentiates T cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Lastly, this combination demonstrates superior anti-tumor activity, compared to either agent alone, in two transplantable tumor models. This study provides clear evidence that RAF inhibitors can modulate T cell function by potentiating T cell activation in vitro and in vivo. Paradoxical activation of ERK signaling in T cells offers one mechanism to explain the enhanced antitumor activity seen when RAF inhibitors are combined with CTLA-4 blockade in preclinical models.

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Section: Introductionmentioning

confidence: 99%

Paradoxical Activation of T Cells via Augmented ERK Signaling Mediated by a RAF Inhibitor

Callahan

Masters

Pratilas

et al. 2014

Cancer Immunology Research

105

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“…S1C), which further revealed increased granularity (side scatter area, SSC-A) and cell size (forward scatter area, FSC-A), indicative of T cell activation (Fig. S1D) (Malik et al, 2009;Pollizzi et al, 2015). No increase in GFP, SSC-A or FSC-A parameters was observed upon co-incubation with non-cognate targets (Fig.…”

Section: Primary Lifeact-egfp T Cells Exhibit a Marked Increase In Fluorescence Following Interaction With Cognate Tumour Cellsmentioning

confidence: 88%

“…2G). By contrast, increases in cell size, as determined by the FSC-A parameter in flow cytometry (Malik et al, 2009;Pollizzi et al, 2015;Jenkins et al, 2015), was indistinguishable between the three subpopulations (Fig. S2F), indicating that the magnitude of the gain in Lifeact-EGFP fluorescence cannot be accounted for simply by an increase in T cell size upon activation (Fig.…”

Section: Primary Lifeact-egfp T Cells Exhibit a Marked Increase In Fluorescence Following Interaction With Cognate Tumour Cellsmentioning

confidence: 96%

The Lifeact-EGFP mouse is a translationally controlled fluorescent reporter of T cell activation

Niño

Tay

Tearle

et al. 2020

Journal of Cell Science

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It has become increasingly evident that T cell functions are subject to translational control in addition to transcriptional regulation. Here, by using live imaging of CD8 + T cells isolated from the Lifeact-EGFP mouse, we show that T cells exhibit a gain in fluorescence intensity following engagement of cognate tumour target cells. The GFP signal increase is governed by Erk1/2-dependent distal T cell receptor (TCR) signalling and its magnitude correlates with IFN-γ and TNF-α production, which are hallmarks of T cell activation. Enhanced fluorescence was due to increased translation of Lifeact-EGFP protein, without an associated increase in its mRNA. Activationinduced gains in fluorescence were also observed in naïve and CD4 + T cells from the Lifeact-EGFP reporter, and were readily detected by both flow cytometry and live cell microscopy. This unique, translationally controlled reporter of effector T cell activation simultaneously enables tracking of cell morphology, F-actin dynamics and activation state in individual migrating T cells. It is a valuable addition to the limited number of reporters of T cell dynamics and activation, and opens the door to studies of translational activity and heterogeneities in functional T cell responses in situ.

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“…Raf-1 functions to activate the extracellular signal-regulated kinase-1/2 (Erk-1/2). Erk1/2 kinase activity results in the activation of the transcription factor Elk1, which contributes to the activation of AP-1 (75,(103)(104)(105)(106).…”

Section: Functional Responses Of Cd4 + T Cellsmentioning

confidence: 99%

The developmental regulator Gon4-like functions within the transcriptional networks that control B lymphopoiesis and CD4+ T cell responses

Hankel¹

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B and T lymphocytes are critical to the adaptive immune response against invading microorganisms. B and T cells develop in the bone marrow and thymus, respectively, and initiate a series of proliferative responses once they encounter their cognate antigen in the peripheral lymphoid organs. These developmental and functional processes are controlled by different networks of transcriptional regulators that repress and activate gene expression. Identifying proteins that activate or repress specific genes and integrating these proteins into their transcriptional networks is critical to understanding lymphocyte development and function. The study of B lymphopoiesis and CD4 + T cell functional responses has greatly increased our understanding of how transcriptional regulators and other proteins cooperate to specify cell fates and responses.While many of the key components of these protein networks have been defined, severalfactors have yet to be described.Chemically induced random mutagenesis is a powerful tool for identifying genes that have critical biological functions. Justy mutant mice were generated by injecting wild-type mice with of N-Ethyl-N-Nitrosourea (ENU), a mutagen, which generated a unique point mutation in the mouse Gon4-like (Gon4l) gene. This mutation was found to specifically blunt B cell development and impair the functional responses of CD4 + T cells.Given that the Gon4l protein contains domains implicated in transcriptional regulation and B lymphopoiesis and T cell responses are regulated transcriptionally, the aim of this project was to characterize T and B lymphocyte populations from Justy mice and provide insights into the mechanisms underlying the regulation of gene expression during these biological processes. The work presented in this dissertation demonstrates that the protein encoded by Gon4l is essential for B lymphopoiesis, likely through the repression of alternate lineage genes. This work also shows that in CD4 + T cells, decreased Gon4l protein expression results in reduced levels of proliferation in response to exogenous IL-2 or T cell receptor (TCR) engagement. Additionally, Justy mutant CD4 + T cells display a reduced ability to generate IFNγ-producing cells in response to Th1 polarization in vitro.Collectively, these defects correlate with elevated levels of genes known to specifically inhibit the above developmental and functional processes. Thus, this dissertation proposes that Gon4l acts as a transcriptional repressor within the protein networks controlling B lymphopoiesis and CD4 + T cell responses.Abstract Approved: ____________________________________ Thesis Supervisor ____________________________________

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Regulation of growth and survival of activated T cells by cell‐transducing inhibitors of Ras

Cited by 4 publications

References 35 publications

Paradoxical Activation of T Cells via Augmented ERK Signaling Mediated by a RAF Inhibitor

Paradoxical Activation of T Cells via Augmented ERK Signaling Mediated by a RAF Inhibitor

The Lifeact-EGFP mouse is a translationally controlled fluorescent reporter of T cell activation

The developmental regulator Gon4-like functions within the transcriptional networks that control B lymphopoiesis and CD4+ T cell responses

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