scholarly journals Itm2a Is Induced during Thymocyte Selection and T Cell Activation and Causes Downregulation of Cd8 When Overexpressed in Cd4+Cd8+ Double Positive Thymocytes

1999 ◽  
Vol 190 (2) ◽  
pp. 217-228 ◽  
Author(s):  
Jacqueline Kirchner ◽  
Michael J. Bevan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
T Cell Activation ◽  
Antigen Processing ◽  
Cell Activation ◽  
Proximal Promoter ◽  
Cell Surface Expression ◽  
Thymocyte Development ◽  
Double Positive

To identify novel genes that are involved in positive selection of thymocytes, we performed polymerase chain reaction (PCR)-based subtractive hybridization between selecting and nonselecting thymi. OT-1 T cell receptor (TCR) transgenic thymocytes on a recombination activating gene (RAG) null background are efficiently selected into the CD8 lineage in H-2b mice (RAG-2−/−OT-1, selecting thymi), but are not selected on a transporter associated with antigen processing (TAP) null background (RAG-2−/−TAP-1−/−OT-1, nonselecting thymi). We report here our studies of one gene, ITM2A, whose expression is dramatically higher in T cells in the selecting thymus. The expression pattern of ITM2A in thymocyte subsets correlates with upregulation during positive selection. In addition, ITM2A expression is higher in the thymus than in either the spleen or lymph nodes, but can be upregulated in peripheral T cells upon activation. ITM2A expression was also induced in RAG-2−/− thymocytes in vivo upon CD3 cross-linking. We demonstrate that ITM2A is a type II membrane glycoprotein that exists as two species with apparent Mr of 45 and 43 kD and appears to localize primarily to large cytoplasmic vesicles and the Golgi apparatus, but is also expressed on the cell surface. Expression on the surface of EL4 cells increases with activation by phorbol myristate acetate (PMA) and ionomycin. Finally, overexpression of ITM2A under control of the lck proximal promoter in mice results in partial downregulation of CD8 in CD4+CD8+ double positive (DP) thymocytes, and a corresponding increase in the number of CD4+CD8lo thymocytes. Possible roles for this novel activation marker in thymocyte development are discussed.

scholarly journals The CD43 130-kD peripheral T-cell activation antigen is downregulated in thymic positive selection

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1725-1732 ◽  
Author(s):  
LG Ellies ◽  
W Tao ◽  
W Fellinger ◽  
HS Teh ◽  
HJ Ziltener
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Class I ◽  
Double Positive ◽  
Mhc Molecules ◽  
Activation Antigen

Abstract Specific glycoforms of CD43, the major O-glycosylated cell-surface protein on T lymphocytes, can affect cell adhesion according to the types of carbohydrate side chains carried. In the peripheral immune system, CD43 130 kD, which carries core 2 O-glycan structures on its surface, is an activation antigen expressed on both CD4 and CD8 single- positive (SP) T cells. We have previously shown that the 115-kD resting and 130-kD activation glycoforms of murine CD43 are differentially regulated on peripheral SP T cells. In this study, we used transgenic mice expressing T-cell receptors (TCRs) specific for antigens presented by class I and class II major histocompatibility complex (MHC) molecules to determine whether CD43 glycoforms are involved in thymocyte differentiation. Positive selection in these mice results in an increase in the production of CD8 and CD4 SP T cells, respectively, which express the transgenic TCR. Positive selection is also accompanied by the upregulation of TCR, CD69, and CD5. Using these markers to define stages of thymocyte maturation, we found that CD43 130 kD was downregulated in the positive selection of CD4 CD8 double- positive thymocytes expressing a class I but not class II MHC- restricted TCR. These data suggest that core 2 glycosyltransferase (C2GnT) modulated expression of CD43 glycoforms may be involved in thymic selection events.

scholarly journals The CD43 130-kD peripheral T-cell activation antigen is downregulated in thymic positive selection

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1725-1732 ◽  
Author(s):  
LG Ellies ◽  
W Tao ◽  
W Fellinger ◽  
HS Teh ◽  
HJ Ziltener
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Class I ◽  
Double Positive ◽  
Mhc Molecules ◽  
Activation Antigen

Specific glycoforms of CD43, the major O-glycosylated cell-surface protein on T lymphocytes, can affect cell adhesion according to the types of carbohydrate side chains carried. In the peripheral immune system, CD43 130 kD, which carries core 2 O-glycan structures on its surface, is an activation antigen expressed on both CD4 and CD8 single- positive (SP) T cells. We have previously shown that the 115-kD resting and 130-kD activation glycoforms of murine CD43 are differentially regulated on peripheral SP T cells. In this study, we used transgenic mice expressing T-cell receptors (TCRs) specific for antigens presented by class I and class II major histocompatibility complex (MHC) molecules to determine whether CD43 glycoforms are involved in thymocyte differentiation. Positive selection in these mice results in an increase in the production of CD8 and CD4 SP T cells, respectively, which express the transgenic TCR. Positive selection is also accompanied by the upregulation of TCR, CD69, and CD5. Using these markers to define stages of thymocyte maturation, we found that CD43 130 kD was downregulated in the positive selection of CD4 CD8 double- positive thymocytes expressing a class I but not class II MHC- restricted TCR. These data suggest that core 2 glycosyltransferase (C2GnT) modulated expression of CD43 glycoforms may be involved in thymic selection events.

scholarly journals A Role for the Tec Family Tyrosine Kinase Txk in T Cell Activation and Thymocyte Selection

1999 ◽  
Vol 190 (10) ◽  
pp. 1427-1438 ◽  
Author(s):  
Connie L. Sommers ◽  
Ronald L. Rabin ◽  
Alexander Grinberg ◽  
Henry C. Tsay ◽  
Joshua Farber ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Positive Selection ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Receptor ◽  
Calcium Signal ◽  
Protein Tyrosine

Summary Recent data indicate that several members of the Tec family of protein tyrosine kinases function in antigen receptor signal transduction. Txk, a Tec family protein tyrosine kinase, is expressed in both immature and mature T cells and in mast cells. By overexpressing Txk in T cells throughout development, we found that Txk specifically augments the phospholipase C (PLC)-γ1–mediated calcium signal transduction pathway upon T cell antigen receptor (TCR) engagement. Although Txk is structurally different from inducible T cell kinase (Itk), another Tec family member expressed in T cells, expression of the Txk transgene could partially rescue defects in positive selection and signaling in itk−/− mice. Conversely, in the itk+/+ (wild-type) background, overexpression of Txk inhibited positive selection of TCR transgenic thymocytes, presumably due to induction of cell death. These results identify a role for Txk in TCR signal transduction, T cell development, and selection and suggest that the Tec family kinases Itk and Txk perform analogous functions.

scholarly journals Mutation in Fas Ligand Impairs Maturation of Thymocytes Bearing Moderate Affinity T Cell Receptors

2003 ◽  
Vol 198 (2) ◽  
pp. 349-360 ◽  
Author(s):  
Tamar E. Boursalian ◽  
Pamela J. Fink
Keyword(s):  
T Cell ◽  
Positive Selection ◽  
T Cell Activation ◽  
T Cell Receptors ◽  
Cell Activation ◽  
Fas Ligand ◽  
Costimulatory Molecule ◽  
Thymocyte Development ◽  
Cell Receptors ◽  
Accessory Molecule

Fas ligand, best known as a death-inducer, is also a costimulatory molecule required for maximal proliferation of mature antigen-specific CD4+ and CD8+ T cells. We now extend the role of Fas ligand by showing that it can also influence thymocyte development. T cell maturation in some, but not all, strains of TCR transgenic mice is severely impaired in thymocytes expressing mutant Fas ligand incapable of interacting with Fas. Mutant Fas ligand inhibits neither negative selection nor death by neglect. Instead, it appears to modulate positive selection of thymocytes expressing both class I– and class II–restricted T cell receptors of moderate affinity for their positively selecting ligands. Fas ligand is therefore an inducer of death, a costimulator of peripheral T cell activation, and an accessory molecule in positive selection.

scholarly journals c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 Have Distinct Roles in CD8+ T Cell Activation

2002 ◽  
Vol 195 (7) ◽  
pp. 811-823 ◽  
Author(s):  
Dietrich Conze ◽  
Troy Krahl ◽  
Norman Kennedy ◽  
Linda Weiss ◽  
Joanne Lumsden ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Surface Expression ◽  
Chain Gene ◽  
Α Chain

The c-Jun NH2-terminal kinase (JNK) signaling pathway is induced by cytokines and stress stimuli and is implicated in cell death and differentiation, but the specific function of this pathway depends on the cell type. Here we examined the role of JNK1 and JNK2 in CD8+ T cells. Unlike CD4+ T cells, the absence of JNK2 causes increased interleukin (IL)-2 production and proliferation of CD8+ T cells. In contrast, JNK1-deficient CD8+ T cells are unable to undergo antigen-stimulated expansion in vitro, even in the presence of exogenous IL-2. The hypoproliferation of these cells is associated with impaired IL-2 receptor α chain (CD25) gene and cell surface expression. The reduced level of nuclear activating protein 1 (AP-1) complexes in activated JNK1-deficient CD8+ T cells can account for the impaired IL-2 receptor α chain gene expression. Thus, JNK1 and JNK2 play different roles during CD8+ T cell activation and these roles differ from those in CD4+ T cells.

scholarly journals Empty conformers of HLA-B preferentially bind CD8 and regulate CD8+ T cell function

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Jie Geng ◽  
John D Altman ◽  
Sujatha Krishnakumar ◽  
Malini Raghavan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Cell Surface Expression ◽  
Antigenic Peptides

When complexed with antigenic peptides, human leukocyte antigen (HLA) class I (HLA-I) molecules initiate CD8+ T cell responses via interaction with the T cell receptor (TCR) and co-receptor CD8. Peptides are generally critical for the stable cell surface expression of HLA-I molecules. However, for HLA-I alleles such as HLA-B*35:01, peptide-deficient (empty) heterodimers are thermostable and detectable on the cell surface. Additionally, peptide-deficient HLA-B*35:01 tetramers preferentially bind CD8 and to a majority of blood-derived CD8+ T cells via a CD8-dependent binding mode. Further functional studies reveal that peptide-deficient conformers of HLA-B*35:01 do not directly activate CD8+ T cells, but accumulate at the immunological synapse in antigen-induced responses, and enhance cognate peptide-induced cell adhesion and CD8+ T cell activation. Together, these findings indicate that HLA-I peptide occupancy influences CD8 binding affinity, and reveal a new set of regulators of CD8+ T cell activation, mediated by the binding of empty HLA-I to CD8.

scholarly journals Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

2019 ◽  
Vol 116 (25) ◽  
pp. 12422-12427 ◽  
Author(s):  
Mingzhu Zheng ◽  
Dan Li ◽  
Zhishan Zhao ◽  
Dmytro Shytikov ◽  
Qin Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
Cell Survival ◽  
Protein Phosphatase ◽  
Essential Role ◽  
Protein Phosphatase 2A ◽  
Thymocyte Development ◽  
Double Positive ◽  
Phosphatase 2A

The development of thymocytes to mature T cells in the thymus is tightly controlled by cellular selection, in which only a small fraction of thymocytes equipped with proper quality of TCRs progress to maturation. It is pivotal to protect the survival of the few T cells, which pass the selection. However, the signaling events, which safeguard the cell survival in thymus, are not totally understood. In this study, protein Ser/Thr phosphorylation in thymocytes undergoing positive selection is profiled by mass spectrometry. The results revealed large numbers of dephosphorylation changes upon T cell receptor (TCR) activation during positive selection. Subsequent substrate analysis pinpointed protein phosphatase 2A (PP2A) as the enzyme responsible for the dephosphorylation changes in developing thymocytes. PP2A catalytic subunit α (Ppp2ca) deletion in the T cell lineage in Ppp2caflox/flox-Lck-Cre mice (PP2A cKO) displayed dysregulated dephosphorylation of apoptosis-related proteins in double-positive (DP) cells and caused substantially decreased numbers of DP CD4+ CD8+ cells. Increased levels of apoptosis in PP2A cKO DP cells were found to underlie aberrant thymocyte development. Finally, the defective thymocyte development in PP2A cKO mice could be rescued by either Bcl2 transgene expression or by p53 knockout. In summary, our work reveals an essential role of PP2A in promoting thymocyte development through the regulation of cell survival.

scholarly journals T-cell receptor α enhancer is inactivated in αβ T lymphocytes

2015 ◽  
Vol 112 (14) ◽  
pp. E1744-E1753 ◽  
Author(s):  
Beatriz del Blanco ◽  
Úrsula Angulo ◽  
Michael S. Krangel ◽  
Cristina Hernández-Munain
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Germ Line ◽  
Cell Receptor ◽  
Thymocyte Development ◽  
Enhancer Activity ◽  
Major Function

The Tcra enhancer (Eα) is essential for Tcra locus germ-line transcription and primary Vα-to-Jα recombination during thymocyte development. We found that Eα is inhibited late during thymocyte differentiation and in αβ T lymphocytes, indicating that it is not required to drive transcription of rearranged Tcra genes. Eα inactivation resulted in the disruption of functional long-range enhancer-promoter interactions and was associated with loss of Eα-dependent histone modifications at promoter and enhancer regions, and reduced expression and recruitment of E2A to the Eα enhanceosome in T cells. Enhancer activity could not be recovered by T-cell activation, by forced expression of E2A or by the up-regulation of this and other transcription factors in the context of T helper differentiation. Our results argue that the major function of Eα is to coordinate the formation of a chromatin hub that drives Vα and Jα germ-line transcription and primary rearrangements in thymocytes and imply the existence of an Eα-independent mechanism to activate transcription of the rearranged Tcra locus in αβ T cells.

scholarly journals Patterns of expression, membrane localization, and effects of ectopic expression suggest a function for MS4a4B, a CD20 homolog in Th1 T cells

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2400-2408 ◽  
Author(s):  
Hui Xu ◽  
Mark S. Williams ◽  
Lisa M. Spain
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ectopic Expression ◽  
Cell Receptor ◽  
Atopic Asthma ◽  
Thymocyte Development ◽  
T Helper 1 ◽  
C Terminus

AbstractThe membrane-spanning 4A (MS4A) family of proteins includes CD20, FcϵRIβ, and HTm4, whose genes are grouped in a chromosomal location that is associated with increased susceptibility to allergy and atopic asthma. One family member, Chandra/MS4a4B, was reported to be expressed in T helper 1 (Th1) T cells but not Th2 T cells. In the present study, Ms4a4b was isolated in a screen of genes differentially expressed during thymocyte development. MS4a4B was detected in immature CD4-CD8-CD44+CD25- thymocytes, turned off during further stages of thymocyte development and reexpressed in mature single-positive thymocytes. MS4a4B expression was found in naive CD8+ and CD4+ peripheral T cells and natural killer (NK) cells but not in B cells. MS4a4B is expressed at the cell surface with its C-terminus located in the cytoplasm. When expressed in a T-cell hybridoma by retroviral vector, MS4a4B protein constitutively associated with lipid raft microdomains, whereas in primary T cells endogenous MS4a4B protein became enriched in rafts after T-cell activation. Overexpression of MS4a4B in primary CD4+ T-cell blasts enhanced T-cell receptor (TCR)-induced Th1 cytokine production. These results suggest that MS4a4B expression is tightly regulated during T-cell development and that MS4a4B expression promotes Th1 function and/or differentiation. (Blood. 2006;107:2400-2408)

scholarly journals Changes in Chromatin Accessibility Across the GM-CSF Promoter upon T Cell Activation Are Dependent on Nuclear Factor κB Proteins

2003 ◽  
Vol 197 (4) ◽  
pp. 413-423 ◽  
Author(s):  
Adele F. Holloway ◽  
Sudha Rao ◽  
Xinxin Chen ◽  
M. Frances Shannon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chromatin Remodeling ◽  
T Cell Activation ◽  
Cell Activation ◽  
Proximal Promoter ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Aberrant Expression ◽  
Gm Csf

Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a key cytokine in myelopoiesis and aberrant expression is associated with chronic inflammatory disease and myeloid leukemias. This aberrant expression is often associated with constitutive nuclear factor (NF)-κB activation. To investigate the relationship between NF-κB and GM-CSF transcription in a chromatin context, we analyzed the chromatin structure of the GM-CSF gene in T cells and the role of NF-κB proteins in chromatin remodeling. We show here that chromatin remodeling occurs across a region of the GM-CSF gene between −174 and +24 upon T cell activation, suggesting that remodeling is limited to a single nucleosome encompassing the proximal promoter. Nuclear NF-κB levels appear to play a critical role in this process. In addition, using an immobilized template assay we found that the ATPase component of the SWI/SNF chromatin remodeling complex, brg1, is recruited to the GM-CSF proximal promoter in an NF-κB–dependent manner in vitro. These results suggest that chromatin remodeling across the GM-CSF promoter in T cells is a result of recruitment of SWI/SNF type remodeling complexes by NF-κB proteins binding to the CD28 response region of the promoter.

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