scholarly journals Ligation of Major Histocompatability Complex (MHC) Class I Molecules on Human T Cells Induces Cell Death through PI-3 Kinase–induced c-Jun NH2-terminal Kinase Activity: A Novel Apoptotic Pathway Distinct from Fas-induced Apoptosis

1997 ◽  
Vol 139 (6) ◽  
pp. 1523-1531 ◽  
Author(s):  
Søren Skov ◽  
Pia Klausen ◽  
Mogens H. Claesson
Keyword(s):  
T Cells ◽  
Kinase Activity ◽  
Dominant Negative ◽  
Class I ◽  
Signal Pathways ◽  
Major Histocompatability Complex ◽  
Jurkat T Cells ◽  
Class I Mhc ◽  
Mhc I ◽  
Induced Apoptosis

Ligation of major histocompatability complex class I (MHC-I) molecules expressed on T cells leads to both growth arrest and apoptosis. The aim of the current study was to investigate the intracellular signal pathways that mediate these effects. MHC-I ligation of human Jurkat T cells induced a morphologically distinct form of apoptosis within 6 h. A specific caspase inhibitor, which inhibited Fas-induced apoptosis, did not affect apoptosis induced by MHC-I ligation. Furthermore, MHC-I–induced apoptosis did not involve cleavage and activation of the poly(ADP- ribose) polymerase (PARP) endonuclease or degradation of genomic DNA into the typical fragmentation ladder, both prominent events of Fas-induced apoptosis. These results suggest that MHC-I ligation of Jurkat T cells induce apoptosis through a signal pathway distinct from the Fas molecule. In our search for other signal pathways leading to apoptosis, we found that the regulatory 85-kD subunit of the phosphoinositide-3 kinase (PI-3) kinase was tyrosine phosphorylated after ligation of MHC-I and the PI-3 kinase inhibitor wortmannin selectively blocked MHC-I–, but not Fas-induced, apoptosis. As the c-Jun NH2-terminal kinase (JNK) can be activated by PI-3 kinase activity, and has been shown to be involved in apoptosis of lymphocytes, we examined JNK activation after MHC-I ligation. Strong JNK activity was observed after MHC-I ligation and the activity was completely blocked by wortmannin. Inhibition of JNK activity, by transfecting cells with a dominant-negative JNKK– MKK4 construct, led to a strong reduction of apoptosis after MHC-I ligation. These results suggest a critical engagement of PI-3 kinase–induced JNK activity in apoptosis induced by MHC-I ligation.

scholarly journals Activation of Stat-3 Is Involved in the Induction of Apoptosis After Ligation of Major Histocompatibility Complex Class I Molecules on Human Jurkat T Cells

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3566-3573 ◽  
Author(s):  
Søren Skov ◽  
Mette Nielsen ◽  
Søren Bregenholt ◽  
Niels Ødum ◽  
Mogens H. Claesson
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Jurkat T Cells ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex

Abstract Activation of Janus tyrosine kinases (Jak) and Signal transducers and activators of transcription (Stat) after ligation of major histocompatibility complex class I (MHC-I) was explored in Jurkat T cells. Cross-linking of MHC-I mediated tyrosine phosphorylation of Tyk2, but not Jak1, Jak2, and Jak3. In addition, the transcription factor Stat-3 was tyrosine phosphorylated in the cytoplasma and subsequently translocated to the cell nucleus. Data obtained by electrophoretic mobility shift assay suggested that the activated Stat-3 protein associates with the human serum-inducible element (hSIE) DNA-probe derived from the interferon-γ activated site (GAS) in the c-fos promoter, a common DNA sequence for Stat protein binding. An association between hSIE and Stat-3 after MHC-I ligation was directly demonstrated by precipitating Stat-3 from nuclear extracts with biotinylated hSIE probe and avidin-coupled agarose. To investigate the function of the activated Stat-3, Jurkat T cells were transiently transfected with a Stat-3 isoform lacking the transactivating domain. This dominant-negative acting Stat-3 isoform significantly inhibited apoptosis induced by ligation of MHC-I. In conclusion, our data suggest the involvement of the Jak/Stat signal pathway in MHC-I–induced signal transduction in T cells.

scholarly journals Activation of Stat-3 Is Involved in the Induction of Apoptosis After Ligation of Major Histocompatibility Complex Class I Molecules on Human Jurkat T Cells

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3566-3573
Author(s):  
Søren Skov ◽  
Mette Nielsen ◽  
Søren Bregenholt ◽  
Niels Ødum ◽  
Mogens H. Claesson
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Jurkat T Cells ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex

Activation of Janus tyrosine kinases (Jak) and Signal transducers and activators of transcription (Stat) after ligation of major histocompatibility complex class I (MHC-I) was explored in Jurkat T cells. Cross-linking of MHC-I mediated tyrosine phosphorylation of Tyk2, but not Jak1, Jak2, and Jak3. In addition, the transcription factor Stat-3 was tyrosine phosphorylated in the cytoplasma and subsequently translocated to the cell nucleus. Data obtained by electrophoretic mobility shift assay suggested that the activated Stat-3 protein associates with the human serum-inducible element (hSIE) DNA-probe derived from the interferon-γ activated site (GAS) in the c-fos promoter, a common DNA sequence for Stat protein binding. An association between hSIE and Stat-3 after MHC-I ligation was directly demonstrated by precipitating Stat-3 from nuclear extracts with biotinylated hSIE probe and avidin-coupled agarose. To investigate the function of the activated Stat-3, Jurkat T cells were transiently transfected with a Stat-3 isoform lacking the transactivating domain. This dominant-negative acting Stat-3 isoform significantly inhibited apoptosis induced by ligation of MHC-I. In conclusion, our data suggest the involvement of the Jak/Stat signal pathway in MHC-I–induced signal transduction in T cells.

Platelet MHC Class I Mediates CD8+ T Cell Suppression During Sepsis

Blood ◽  
2021 ◽  
Author(s):  
Li Guo ◽  
Sikui Shen ◽  
Jesse W Rowley ◽  
Neal D. Tolley ◽  
Wenwen Jia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Cd8 T Cell ◽  
Class I ◽  
Functional Responses ◽  
Class I Mhc ◽  
Mhc I

Circulating platelets interact with leukocytes to modulate host immune and thrombotic responses. In sepsis, platelet-leukocyte interactions are increased, and have been associated with adverse clinical events, including increased platelet-T cell interactions. Sepsis is associated with reduced CD8+ T cell numbers and functional responses, but whether platelets regulate CD8+ T cell responses during sepsis remains unknown. In our current study, we systemically evaluated platelet antigen internalization and presentation through major histocompatibility complex class I (MHC-I) and their effects on antigen specific CD8+ T cells in sepsis in vivo and ex vivo. We discovered that both human and murine platelets internalize and proteolyze exogenous antigens, generating peptides that are loaded onto MHC-I. The expression of platelet MHC-I, but not platelet MHC-II, is significantly increased in human and murine platelets during sepsis and in human megakaryocytes stimulated with agonists generated systemically during sepsis (e.g., IFN-g and LPS). Upregulation of platelet MHC-I during sepsis increases antigen cross-presentation and interactions with CD8+ T cells in an antigen-specific manner. Using a platelet lineage specific MHC-I deficient mouse strain (B2mf/f--Pf4Cre), we demonstrate that platelet MHC-I regulates antigen-specific CD8+ T cell proliferation in vitro, as well as the number and functional responses of CD8+ T cells in vivo during sepsis. Loss of platelet MHC-I reduced sepsis-associated mortality in mice in an antigen specific setting. These data identify a new mechanism by which platelets, through MHC-I, process and cross-present antigens, engage antigen specific CD8+ T cells, and regulate CD8+ T cell number, functional responses, and outcomes during sepsis.

scholarly journals Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation

2021 ◽  
Vol 12 ◽  
Author(s):  
Karthik Dhatchinamoorthy ◽  
Jeff D. Colbert ◽  
Kenneth L. Rock
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Antigen Presentation ◽  
Cd8 T Cells ◽  
Class I ◽  
Immune Control ◽  
Class I Mhc ◽  
Mhc I ◽  
Mhc Class I Antigen ◽  
Underlying Mechanisms

Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell's expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8 T cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. In order for many cancers to arise and progress, they need to evolve mechanisms to avoid elimination by CD8 T cells. MHC I molecules are not essential for cell survival and therefore one mechanism by which cancers can evade immune control is by losing MHC I antigen presentation machinery (APM). Not only will this impair the ability of natural immune responses to control cancers, but also frustrate immunotherapies that work by re-invigorating anti-tumor CD8 T cells, such as checkpoint blockade. Here we review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers. We discuss new insights into some common underlying mechanisms through which some cancers inactivate the MHC I pathway and consider some possible strategies to overcome this limitation in ways that could restore immune control of tumors and improve immunotherapy.

scholarly journals Self MHC class I–licensed NK cells enhance adaptive CD8 T-cell viral immunity

Blood ◽  
2011 ◽  
Vol 117 (19) ◽  
pp. 5133-5141 ◽  
Author(s):  
Michael D. Stadnisky ◽  
Xuefang Xie ◽  
Ebony R. Coats ◽  
Timothy N. Bullock ◽  
Michael G. Brown
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Class I ◽  
Inhibitory Receptor ◽  
Class I Mhc ◽  
Mhc I

AbstractMHC class I (MHC I) is essential to NK- and T-cell effector and surveillance functions. However, it is unknown whether MHC I polymorphism influences adaptive immunity through NK cells. Previously, we found that MHC I Dk, a cognate ligand for the Ly49G2 inhibitory receptor, was essential to NK control of murine (M)CMV infection. Here we assessed the significance of NK inhibitory receptor recognition of MCMV on CD8 T cells in genetically defined MHC I Dk disparate mice. We observed that Dk-licensed Ly49G2+ NK cells stabilized and then enhanced conventional dendritic cells (cDCs) recovery after infection. Furthermore, licensed NK support of cDC recovery was essential to enhance the tempo, magnitude, and effector activity of virus-specific CD8 T cells. Minimal cDC and CD8 T-cell number differences after low-dose MCMV in Dk disparate animals further implied that licensed NK recognition of MCMV imparted qualitative cDC changes to enhance CD8 T-cell priming.

Akt Regulates the Activation-Induced Apoptosis of T Cells Mediated by HIV-1 gp120.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3109-3109
Author(s):  
Appakkudal R. Anand ◽  
Ramesh K. Ganju
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Vector Control ◽  
Dominant Negative ◽  
Wild Type ◽  
Jurkat T Cells ◽  
Induced Apoptosis ◽  
Hiv 1

Abstract Multiple mechanisms contribute to the loss of CD4+ T cells in HIV-1 infected individuals. Activation-induced apoptosis of bystander T cells mediated by HIV-1 gp120 is one of the critical mechanisms leading to T cell loss in AIDS. Clinical studies have shown that T cells in the lymph nodes of HIV-1 infected individuals undergo activation-induced apoptosis. In the present study, we used a model where T cells undergo apoptosis after HIV-1 gp120/CD4 cross-linking in conjunction with CD3/T cell antigen receptor activation. We have shown that treatment with HIV-1 gp120 (10 nM) and anti-gp120 MoAb induces approximately 20–25% apoptosis in Jurkat T cells in the presence of immobilized anti-CD3 antibody. However, the molecular mechanism by which HIV-1 gp120 mediates the apoptosis of T cells is still unclear. We have also examined the role of Akt/Protein kinase B in HIV-1 gp120-induced apoptosis. Akt is a cell survival molecule that has been shown to block cell death. We observed a decrease in Akt phosphorylation upon gp120 treatment of Jurkat T cells and peripheral blood mononuclear cells (PBMCs). In contrast, only CD3 stimulation was shown to increase the phosphorylation of Akt. To further confirm the role of Akt in gp120-induced apoptosis, Jurkat T cells were transfected with HA epitope-tagged wild type Akt, dominant-negative Akt that lacks kinase activity, or with a control vector. The transfected cells were treated with gp120 and apoptosis was evaluated by Annexin-PI staining. The T cells expressing wild type Akt showed reduced gp120 apoptosis as compared to the vector control-expressing cells. Conversely, expression of a dominant-negative mutant of Akt accelerated cell death as compared to the vector control. We then further assessed the role of upstream regulators of Akt, such as PI-3 kinase. In this regard, we have shown that inhibition of PI-3 kinase leads to enhanced gp120-induced apoptosis. At present, we are elucidating downstream effectors of the Akt pathway. Taken together, these studies suggest that Akt plays a key role in HIV-1 gp120-induced apoptosis, and that identification of Akt-mediated signaling pathways may provide novel therapeutic targets to combat immune deficiency in AIDS.

scholarly journals A flexible MHC class I multimer loading system for large-scale detection of antigen-specific T cells

2018 ◽  
Vol 215 (5) ◽  
pp. 1493-1504 ◽  
Author(s):  
Jolien J. Luimstra ◽  
Malgorzata A. Garstka ◽  
Marthe C.J. Roex ◽  
Anke Redeker ◽  
George M.C. Janssen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Large Scale ◽  
Time Frame ◽  
Class I ◽  
Cell Transplant ◽  
Class I Mhc ◽  
Mhc I ◽  
Isolation And Characterization

Adaptive immunity is initiated by T cell recognition of specific antigens presented by major histocompatibility complexes (MHCs). MHC multimer technology has been developed for the detection, isolation, and characterization of T cells in infection, autoimmunity, and cancer. Here, we present a simple, fast, flexible, and efficient method to generate many different MHC class I (MHC I) multimers in parallel using temperature-mediated peptide exchange. We designed conditional peptides for HLA-A*02:01 and H-2Kb that form stable peptide–MHC I complexes at low temperatures, but dissociate when exposed to a defined elevated temperature. The resulting conditional MHC I complexes, either alone or prepared as ready-to-use multimers, can swiftly be loaded with peptides of choice without additional handling and within a short time frame. We demonstrate the ease and flexibility of this approach by monitoring the antiviral immune constitution in an allogeneic stem cell transplant recipient and by analyzing CD8+ T cell responses to viral epitopes in mice infected with lymphocytic choriomeningitis virus or cytomegalovirus.

The role of cbl family of ubiquitin ligases in gastric cancer exosome-induced apoptosis of Jurkat T cells

2009 ◽  
pp. 1-8
Author(s):  
Jing-Lei Qu ◽  
Xiu-Juan Qu ◽  
Ming-Fang Zhao ◽  
Yue-E Teng ◽  
Ye Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Ubiquitin Ligases ◽  
Jurkat T Cells ◽  
Induced Apoptosis

Ligand Design for Specific MHC Class I Molecules on the Cell Surface

2020 ◽  
Author(s):  
Xizheng Sun ◽  
Reika Tokunaga ◽  
Yoko Nagai ◽  
Ryo Miyahara ◽  
Akihiro Kishimura ◽  
...  
Keyword(s):  
Cell Surface ◽  
Mhc Class I ◽  
Targeted Delivery ◽  
Peptide Ligands ◽  
Class I ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
High Binding Affinity ◽  
Mhc Class I Molecules

<p><a></a><a></a><a>We have validated that ligand peptides designed from antigen peptides could be used for targeting specific major histocompatibility complex class I (MHC-I)</a> molecules on cell surface. To design the ligand peptides, we used reported antigen peptides for each MHC-I molecule with high binding affinity. From the crystal structure of the peptide/MHC-I complexes, we determined a modifiable residue in the antigen peptides and replaced this residue with a lysine with an ε-amine group modified with functional molecules. The designed ligand peptides successfully bound to cells expressing the corresponding MHC-I molecules via exchange of peptides bound to the MHC-I. We demonstrated that the peptide ligands could be used to transport a protein or a liposome to cells expressing the corresponding MHC-I. The present strategy may be useful for targeted delivery to cells overexpressing MHC-I, which have been observed autoimmune diseases.</p>

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