T-cell Activation Leads to Rapid Stimulation of Translation Initiation Factor eIF2B and Inactivation of Glycogen Synthase Kinase-3

Activation of T cells requires a rapid surge in cellular protein synthesis. However, the role of translation initiation in the early induction of specific genes remains unclear. Here we show human translation initiation factor eIF3 interacts with select immune system related mRNAs including those encoding the T cell receptor (TCR) subunits TCRA and TCRB. Binding of eIF3 to the TCRA and TCRB mRNA 3'-untranslated regions (3'-UTRs) depends on CD28 coreceptor signaling and regulates a burst in TCR translation required for robust T cell activation. Use of the TCRA or TCRB 3'-UTRs to control expression of an anti-CD19 chimeric antigen receptor (CAR) improves the ability of CAR-T cells to kill tumor cells in vitro. These results identify a new mechanism of eIF3-mediated translation control that can aid T cell engineering for immunotherapy applications.

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Robust T cell activation requires an eIF3-driven burst in T cell receptor translation

10.1101/2021.10.04.463005 ◽

2021 ◽

Author(s):

Dasmanthie DeSilva ◽

Lucas Ferguson ◽

Grant Chin ◽

Benjamin Smith ◽

Ryan Apathy ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

T Cell Activation ◽

Translation Initiation ◽

Cell Activation ◽

Cell Receptor ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Translation Control

Activation of T cells requires a rapid surge in cellular protein synthesis. However, the role of translation initiation in the early induction of specific genes remains unclear. Here we show human translation initiation factor eIF3 interacts with select immune system related mRNAs including those encoding the T cell receptor (TCR) subunits TCRA and TCRB. Binding of eIF3 to the TCRA and TCRB mRNA 3’-untranslated regions (3’-UTRs) depends on CD28 coreceptor signaling and regulates a burst in TCR translation required for robust T cell activation. Use of the TCRA or TCRB 3’-UTRs to control expression of an anti-CD19 chimeric antigen receptor (CAR) improves the ability of CAR-T cells to kill tumor cells in vitro. These results identify a new mechanism of eIF3-mediated translation control that can aid T cell engineering for immunotherapy applications.

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Regulation of eukaryotic translation initiation factor expression during T-cell activation

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ◽

10.1016/0167-4889(93)90053-r ◽

1993 ◽

Vol 1176 (3) ◽

pp. 257-264 ◽

Cited By ~ 31

Author(s):

Thomas R. Boal ◽

John A. Chiorini ◽

Roger B. Cohen ◽

Suzanne Miyamoto ◽

Robert M. Frederickson ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Translation Initiation ◽

Cell Activation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Eukaryotic Translation Initiation Factor ◽

Eukaryotic Translation ◽

Factor Expression ◽

Eukaryotic Translation Initiation

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Glycogen Synthase Kinase-3 Modulates Cbl-b and Constrains T Cell Activation

The Journal of Immunology ◽

10.4049/jimmunol.1600396 ◽

2017 ◽

Vol 199 (12) ◽

pp. 4056-4065 ◽

Cited By ~ 5

Author(s):

Charles W. Tran ◽

Samuel D. Saibil ◽

Thierry Le Bihan ◽

Sara R. Hamilton ◽

Karl S. Lang ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3

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Stimulation of GTP Cyclohydrolase I by Phosphorylation Upon T Cell Activation

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.lb187 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Wei Chen ◽

Li Li ◽

Torben Brod ◽

Omar Saeed ◽

Serguei Dikalov ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Gtp Cyclohydrolase I ◽

Gtp Cyclohydrolase ◽

Stimulation Of

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Binding of eukaryotic translation initiation factor 4E (eIF4E) to eIF4G represses translation of uncapped mRNA.

Molecular and Cellular Biology ◽

10.1128/mcb.17.12.6876 ◽

1997 ◽

Vol 17 (12) ◽

pp. 6876-6886 ◽

Cited By ~ 52

Author(s):

S Z Tarun ◽

A B Sachs

Keyword(s):

Translation Initiation ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Eukaryotic Translation Initiation Factor ◽

Eukaryotic Translation ◽

Eukaryotic Translation Initiation ◽

Stimulation Of

mRNA translation in crude extracts from the yeast Saccharomyces cerevisiae is stimulated by the cap structure and the poly(A) tail through the binding of the cap-binding protein eukaryotic translation initiation factor 4E (eIF4E) and the poly(A) tail-binding protein Pab1p. These proteins also bind to the translation initiation factor eIF4G and thereby link the mRNA to the general translational apparatus. In contrast, uncapped, poly(A)-deficient mRNA is translated poorly in yeast extracts, in part because of the absence of eIF4E and Pab1p binding sites on the mRNA. Here, we report that uncapped-mRNA translation is also repressed in yeast extracts due to the binding of eIF4E to eIF4G. Specifically, we find that mutations which weaken the eIF4E binding site on the yeast eIF4G proteins Tif4631p and Tif4632p lead to temperature-sensitive growth in vivo and the stimulation of uncapped-mRNA translation in vitro. A mutation in eIF4E which disturbs its ability to interact with eIF4G also leads to a stimulation of uncapped-mRNA translation in vitro. Finally, overexpression of eIF4E in vivo or the addition of excess eIF4E in vitro reverses these effects of the mutations. These data support the hypothesis that the eIF4G protein can efficiently stimulate translation of exogenous uncapped mRNA in extracts but is prevented from doing so as a result of its association with eIF4E. They also suggest that some mRNAs may be translationally regulated in vivo in response to the amount of free eIF4G in the cell.

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Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency

Journal of Clinical Immunology ◽

10.1007/s10875-019-00735-z ◽

2019 ◽

Vol 40 (2) ◽

pp. 277-288 ◽

Cited By ~ 2

Author(s):

Hassan Abolhassani ◽

Yasser M. El-Sherbiny ◽

Gururaj Arumugakani ◽

Clive Carter ◽

Stephen Richards ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Clinical Phenotype ◽

Compound Heterozygous ◽

Dominant Phenotype ◽

Cytokine Responses ◽

Whole Exome ◽

Stimulation Of

Abstract Background Inducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novel ICOS mutations resulting in a common variable immunodeficiency (CVID)–like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte–associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition. Methods A combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA. Results Four novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1β, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ stimulation. This was associated with skewing of CD4+ T cells towards Th1 phenotype and increased expression of ICOSL on monocytes. Lastly, reduced CTLA4 expression was found in 2 patients. One patient treated with ustekinumab for pancytopenia due to granulomatous bone marrow infiltration failed to respond to this targeted therapy. Conclusions ICOS deficiency is associated with defective T cell activation, with simultaneously enhanced stimulation of monocytes. The latter is likely to result from a lack of ICOS/ICOSL interaction which might be necessary to provide negative feedback which limits monocytes activation.

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Autocrine stimulation of P2Y1 receptors is part of the purinergic signaling mechanism that regulates T cell activation

Purinergic Signalling ◽

10.1007/s11302-019-09653-6 ◽

2019 ◽

Vol 15 (2) ◽

pp. 127-137 ◽

Cited By ~ 1

Author(s):

Tobias Woehrle ◽

Carola Ledderose ◽

Jessica Rink ◽

Christian Slubowski ◽

Wolfgang G. Junger

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Purinergic Signaling ◽

Signaling Mechanism ◽

Autocrine Stimulation ◽

Stimulation Of

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Induction of c-ets and c-fos gene expression upon antigenic stimulation of a T cell hybridoma with inducible cytolytic capacity.

Journal of Experimental Medicine ◽

10.1084/jem.166.3.810 ◽

1987 ◽

Vol 166 (3) ◽

pp. 810-815 ◽

Cited By ~ 6

Author(s):

Y Kaufmann ◽

T Silverman ◽

B Z Levi ◽

K Ozato

Keyword(s):

Gene Expression ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Specific Antigen ◽

Functional Differentiation ◽

Mrna Levels ◽

Cellular Oncogenes ◽

Differentiation Of Lymphocytes ◽

Stimulation Of

Expression of cellular oncogenes was studied in a T cell hybridoma that undergoes cytolytic activation when stimulated by specific antigen or by anti-Thy-1 antibody. The activation occurs without induction of hybridoma proliferation, providing a model to examine oncogene expression during functional differentiation of lymphocytes. We found that c-fos and c-ets-1 mRNAs were transiently induced at high levels in the hybridoma 30 min and 4 h after stimulation, respectively. c-myc and c-ets-2 oncogenes were constitutively expressed in the hybridoma and their mRNA levels were unaffected during 4 h of stimulation, although c-myc expression was reduced in the later stage of stimulation. Inhibitors of T cell activation, cyclosporin A and anti-LFA-1 antibody, blocked the induction of c-fos and c-ets-1 mRNAs without reducing the levels of c-myc and c-ets-2. The results indicate that the functional activation of the CTL hybridoma is associated with induction of c-fos and c-ets-1 genes.

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