Protein abundance of the cytokine receptor γc controls the thymic generation of innate-like T cells

The thymus generates T cells with diverse specificities and functions. To assess the contribution of cytokine receptors to the differentiation of T cell subsets in the thymus, we constructed conditional knockout mice in which IL-7Rα or common cytokine receptor γ chain (γc) genes were deleted in thymocytes just before positive selection. We found that γc expression was required to signal the differentiation of MHC class I (MHC-I)–specific thymocytes into CD8+ cytotoxic lineage T cells and into invariant natural killer T cells but did not signal the differentiation of MHC class II (MHC-II)–specific thymocytes into CD4+ T cells, even into regulatory Foxp3+CD4+ T cells which require γc signals for survival. Importantly, IL-7 and IL-15 were identified as the cytokines responsible for CD8+ cytotoxic T cell lineage specification in vivo. Additionally, we found that small numbers of aberrant CD8+ T cells expressing Runx3d could arise without γc signaling, but these cells were developmentally arrested before expressing cytotoxic lineage genes. Thus, γc-transduced cytokine signals are required for cytotoxic lineage specification in the thymus and for inducing the differentiation of MHC-I–selected thymocytes into functionally mature T cells.

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In Vitro Evidence That Cytokine Receptor Signals Are Required for Differentiation of Double Positive Thymocytes into Functionally Mature CD8+ T Cells

Journal of Experimental Medicine ◽

10.1084/jem.20021765 ◽

2003 ◽

Vol 197 (4) ◽

pp. 475-487 ◽

Cited By ~ 91

Author(s):

Qing Yu ◽

Batu Erman ◽

Avinash Bhandoola ◽

Susan O. Sharrow ◽

Alfred Singer

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Glucose Transporter ◽

Experimental System ◽

Cytokine Receptor ◽

Cytokine Receptors ◽

Double Positive ◽

Thymocyte Differentiation ◽

Tcr Signals

CD4+8+ double positive (DP) thymocytes differentiate into CD4+ and CD8+ mature T cells in response to TCR signals. However, TCR signals that are initiated in DP thymocytes are unlikely to persist throughout all subsequent differentiation steps, suggesting that other signals must sustain thymocyte differentiation after TCR signaling has ceased. Using an in vitro experimental system, we now demonstrate that cytokine receptor signals, such as those transduced by IL-7 receptors, are required for differentiation of signaled DP thymocytes into functionally mature CD8+ T cells as they: (a) up-regulate Bcl-2 expression to maintain thymocyte viability; (b) enhance CD4 gene silencing; (c) promote functional maturation;and (d) up-regulate surface expression of glucose transporter molecules, which improve nutrient uptake and increase metabolic activity. IL-7Rs appear to be unique among cytokine receptors in maintaining the viability of newly generated CD4−8+ thymocytes, whereas several different cytokine receptors can provide the trophic/differentiative signals for subsequent CD8+ thymocyte differentiation and maturation. Thus, cytokine receptors provide both survival and trophic/differentiative signals with varying degrees of redundancy that are required for differentiation of signaled DP thymocytes into functionally mature CD8+ T cells.

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A Point Mutation of Tyr-759 in Interleukin 6 Family Cytokine Receptor Subunit gp130 Causes Autoimmune Arthritis

Journal of Experimental Medicine ◽

10.1084/jem.20020619 ◽

2002 ◽

Vol 196 (7) ◽

pp. 979-990 ◽

Cited By ~ 148

Author(s):

Toru Atsumi ◽

Katsuhiko Ishihara ◽

Daisuke Kamimura ◽

Hideto Ikushima ◽

Takuya Ohtani ◽

...

Keyword(s):

T Cells ◽

Point Mutation ◽

Fas Ligand ◽

Tyrosine Phosphatase ◽

Disease Onset ◽

Cytokine Receptor ◽

Joint Disease ◽

Clonal Deletion ◽

Activated T Cells ◽

Autoantibody Production

We generated a mouse line in which the src homology 2 domain–bearing protein tyrosine phosphatase (SHP)-2 binding site of gp130, tyrosine 759, was mutated to phenylalanine (gp130F759/F759). The gp130F759/F759 mice developed rheumatoid arthritis (RA)-like joint disease. The disease was accompanied by autoantibody production and accumulated memory/activated T cells and myeloid cells. Before the disease onset, the T cells were hyperresponsive and thymic selection and peripheral clonal deletion were impaired. The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130F759/F759 T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation. Finally, we showed that disease development was dependent on lymphocytes. These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease.

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CD8+T Cells in HIV Disease Exhibit Cytokine Receptor Perturbation and Poor T Cell Receptor Activation but Are Responsive to γ‐Chain Cytokine–Driven Proliferation

The Journal of Infectious Diseases ◽

10.1086/500471 ◽

2006 ◽

Vol 193 (6) ◽

pp. 879-887 ◽

Cited By ~ 20

Author(s):

Rajendra Pahwa ◽

Thomas W. McCloskey ◽

Olga C. Aroniadis ◽

Natasa Strbo ◽

Subramaniam Krishnan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Cell Receptor ◽

Receptor Activation ◽

Cytokine Receptor ◽

Hiv Disease

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NEAT-seq: Simultaneous profiling of intra-nuclear proteins, chromatin accessibility, and gene expression in single cells

10.1101/2021.07.29.454078 ◽

2021 ◽

Author(s):

Amy F Chen ◽

Benjamin Parks ◽

Arwa Kathiria ◽

Benjamin Ober-Reynolds ◽

Jorg Goronzy ◽

...

Keyword(s):

T Cells ◽

High Throughput Sequencing ◽

Target Genes ◽

Nuclear Protein ◽

Single Cells ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

T Cell Subsets ◽

Protein Abundance ◽

Joint Measurement

Oligonucleotide-conjugated antibodies have allowed for joint measurement of surface protein abundance and the transcriptome in single cells using high-throughput sequencing. Extending these measurements to gene regulatory proteins in the nucleus would provide a powerful means to link changes in abundance of trans-acting TFs to changes in activity of cis-acting elements and expression of target genes. Here, we introduce Nuclear protein Epitope, chromatin Accessibility, and Transcriptome sequencing (NEAT-seq), a technique to simultaneously measure nuclear protein abundance, chromatin accessibility, and the transcriptome in single cells. We apply this technique to profile CD4 memory T cells using a panel of master transcription factors (TFs) that drive distinct helper T cell subsets and regulatory T cells (Tregs) and identify examples of TFs with regulatory activity gated by three distinct mechanisms: transcription, translation, and regulation of chromatin binding. Furthermore, we identify regulatory elements and target genes associated with each TF, which we use to link a non-coding GWAS SNP within a GATA motif to both strong allele-specific chromatin accessibility in cells expressing high levels of GATA3 protein, and a putative target gene.

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ANTIBODIES WHICH TARGET THE COMMON CYTOKINE RECEPTOR GAMMA (γc) CHAIN ENHANCE ACTIVATION-INDUCED APOPTOSIS OF ALLOSPECIFIC CD8+ T CELLS

Transplantation Journal ◽

10.1097/00007890-199904150-00088 ◽

1999 ◽

Vol 67 (7) ◽

pp. S21 ◽

Cited By ~ 1

Author(s):

Z Dai ◽

A Arakelov ◽

M. Wagener ◽

B. T. Konieczny ◽

F G Lakkis

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cytokine Receptor ◽

The Common ◽

Induced Apoptosis

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Faculty Opinions recommendation of Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732770144.793544351 ◽

2018 ◽

Author(s):

Arthur Hurwitz ◽

Dhan Chand

Keyword(s):

T Cells ◽

Cytokine Receptor ◽

Receptor Complexes ◽

Selective Targeting ◽

Engineered T Cells

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Expression of JAK3 Sensitive Na+ Coupled Glucose Carrier SGLT1 in Activated Cytotoxic T Lymphocytes

Cellular Physiology and Biochemistry ◽

10.1159/000447827 ◽

2016 ◽

Vol 39 (3) ◽

pp. 1209-1228 ◽

Cited By ~ 9

Author(s):

Shefalee K. Bhavsar ◽

Yogesh Singh ◽

Piyush Sharma ◽

Vishal Khairnar ◽

Zohreh Hosseinzadeh ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Cell Membrane ◽

Glucose Uptake ◽

Xenopus Oocytes ◽

Cytotoxic T Cells ◽

Brefeldin A ◽

Protein Abundance ◽

Jurkat T Cells ◽

Glucose Carrier

Background: Similar to tumor cells, activated T-lymphocytes generate ATP mainly by glycolytic degradation of glucose. Lymphocyte glucose uptake involves non-concentrative glucose carriers of the GLUT family. In contrast to GLUT isoforms, Na+-coupled glucose-carrier SGLT1 accumulates glucose against glucose gradients and is effective at low extracellular glucose concentrations. The present study explored expression and regulation of SGLT1 in activated murine splenic cytotoxic T cells (CTLs) and human Jurkat T cells. Methods: FACS analysis, immunofluorescence, confocal microscopy, chemiluminescence and Western blotting were employed to estimate SGLT1 expression, function and regulation in lymphocytes, as well as dual electrode voltage clamp in SGLT1 ± JAK3 expressing Xenopus oocytes to quantify the effect of janus kinase3 (JAK3) on SGLT1 function. Results: SGLT1 is expressed in murine CTLs and also in human Jurkat T cells. 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose uptake was significantly decreased by SGLT1-blocker phloridzin (0.2 mM) and by pharmacological inhibition of JAK3 with WHI-P131 (156 µM), WHI-P154 (11.2 µM) and JAK3 inhibitor VI (0.5 µM). Electrogenic glucose transport (Iglucose) in Xenopus oocytes expressing human SGLT1 was increased by additional expression of human wild type JAK3, active A568VJAK3 but not inactive K851AJAK3. Coexpression of JAK3 enhanced the maximal transport rate without significantly modifying affinity of the carrier. Iglucose in SGLT1+JAK3 expressing oocytes was significantly decreased by WHI-P154 (11.2 µM). JAK3 increased the SGLT1 protein abundance in the cell membrane. Inhibition of carrier insertion by brefeldin A (5 µM) in SGLT1+JAK3 expressing oocytes resulted in a decline of Iglucose, which was similar in presence and absence of JAK3. Conclusions: SGLT1 is expressed in murine cytotoxic T cells and human Jurkat T cells and significantly contributes to glucose uptake in those cells post activation. JAK3 up-regulates SGLT1 activity by increasing the carrier protein abundance in the cell membrane, an effect enforcing cellular glucose uptake into activated lymphocytes and thus contributing to the immune response.

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