Recruitment of cytoplasmic molecules to the tyrosine kinase Zap-70 in T cells

1997 ◽  
Vol 56 (1-3) ◽  
pp. 67
Author(s):  
D Rhoda
Keyword(s):  
T Cells ◽  
Tyrosine Kinase

scholarly journals Development of Autologous, Oligoclonal, Poorly Functioning T Lymphocytes in a Patient With Autosomal Recessive Severe Combined Immunodeficiency Caused by Defects of the Jak3 Tyrosine Kinase

Blood ◽  
1998 ◽  
Vol 91 (3) ◽  
pp. 949-955 ◽  
Author(s):  
Duilio Brugnoni ◽  
Luigi D. Notarangelo ◽  
Alessandra Sottini ◽  
Paolo Airò ◽  
Marta Pennacchio ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Tyrosine Kinase ◽  
Cd4 T Cells ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
T Helper ◽  
T Helper 1 ◽  
In Vitro Susceptibility ◽  
And Function

Abstract Defects of the common gamma chain subunit of the cytokine receptors (γc) or of Jak3, a tyrosine kinase required for γc signal transduction, result in T−B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (>3,000/μL) of autologous CD3+CD4+ T cells. These cells showed a primed/activated phenotype (CD45R0+ Fas+HLA-DR+ CD62Llo), defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in γc-/y and in Jak3−/−mice, in which a population of activated, anergic T cells (predominantly CD4+) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4+ T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8+ T cells, nor do they fully restore the functional properties of CD4+ T lymphocytes.

scholarly journals Therapeutic efficacy of an immune stimulatory gene therapy strategy in a mouse model of high grade brainstem glioma

2019 ◽  
Author(s):  
Flor M. Mendez ◽  
Padma Kadiyala ◽  
Felipe J. Nunez ◽  
Stephen Carney ◽  
Fernando Nunez ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
T Cells ◽  
Mouse Model ◽  
Tyrosine Kinase ◽  
Thymidine Kinase ◽  
Tumor Antigen ◽  
Therapeutic Efficacy ◽  
Brainstem Glioma ◽  
Adenoviral Delivery

AbstractPurposeDiffuse intrinsic pontine glioma (DIPG) bears a dismal prognosis. A genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, ACVR1-G328V (mACVR1), was developed for testing an immune-stimulatory gene therapy.Experimental DesignWe utilized the Sleeping Beauty transposase system to generate an endogenous mouse model of mACVR1 brainstem glioma. Histology was used to characterize and validate the model. We performed RNAseq analysis on neurospheres (NS) harboring mACVR1. mACVR1 NS were implanted into the pons of immune competent mice to test the therapeutic efficacy and toxicity of immune stimulatory gene therapy using adenoviruses expressing thymidine kinase (TK) and fms-like tyrosine kinase 3 ligand (Flt3L). mACVR1 NS expressing the surrogate tumor antigen ovalbumin were generated to investigate if TK/Flt3L treatment induces the recruitment of tumor-antigen specific T cells.ResultsHistological analysis of mACVR1 tumors indicates that they are localized in the brainstem and have increased downstream signaling of bone morphogenetic pathway as demonstrated by increased phospho-smad1/5 and Id1 levels. Transcriptome analysis of mACVR1 NS identified an increase in the transforming growth factor beta (TGF-β) signaling pathway and the regulation of cell differentiation. Adenoviral delivery of TK/Flt3L in mice bearing brainstem gliomas resulted in anti-tumor immunity, recruitment of anti-tumor specific T cells and increased median survival.ConclusionsThis study provides insights into the phenotype and function of the tumor immune microenvironment in a mouse model of brainstem glioma harboring mACVR1. Immune stimulatory gene therapy targeting the hosts’ anti-tumor immune response inhibits tumor progression and increases median survival of mice bearing mACVR1 tumors.Translational RelevanceThe therapeutic efficacy of anti-DIPG immune responses is limited due to a low number of immune cells in the tumor microenvironment. We have uncovered a novel treatment strategy that utilizes adenoviral delivery of therapeutic genes, thymidine kinase (TK) and fms tyrosine kinase 3 ligand (Flt3L) into the tumor, eliciting a reprograming of the host’s own immune system to recognize and kill tumor cells. We demonstrate that TK/Flt3L therapy generates an effective anti-tumor response and can be safely delivered into the brainstem. This treatment approach could provide a novel translational approach towards potentiating an anti-DIPG immune response to overcome the current limitations in the treatment of patients with DIPG.

scholarly journals Fms-Like Tyrosine Kinase 3 Ligand Controls Formation of Regulatory T Cells in Autoimmune Arthritis

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e54884 ◽  
Author(s):  
Mattias N. D. Svensson ◽  
Sofia E. M. Andersson ◽  
Malin C. Erlandsson ◽  
Ing-Marie Jonsson ◽  
Anna-Karin H. Ekwall ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Tyrosine Kinase ◽  
Autoimmune Arthritis

Phosphatidylinositol (PI) 3-kinase and PI 4-kinase binding to the CD4-p56lck complex: the p56lck SH3 domain binds to PI 3-kinase but not PI 4-kinase

1993 ◽  
Vol 13 (12) ◽  
pp. 7708-7717
Author(s):  
K V Prasad ◽  
R Kapeller ◽  
O Janssen ◽  
H Repke ◽  
J S Duke-Cohan ◽  
...  
Keyword(s):  
T Cells ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Sh3 Domain ◽  
Sh2 Domain ◽  
Activation Process ◽  
Lipid Kinase ◽  
Sh3 Domains ◽  
Protein Tyrosine ◽  
Hiv 1

CD4 serves as a receptor for major histocompatibility complex class II antigens and as a receptor for the human immunodeficiency virus type 1 (HIV-1) viral coat protein gp120. It is coupled to the protein-tyrosine kinase p56lck, an interaction necessary for an optimal response of certain T cells to antigen. In addition to the protein-tyrosine kinase domain, p56lck possesses Src homology 2 and 3 (SH2 and SH3) domains as well as a unique N-terminal region. The mechanism by which p56lck generates intracellular signals is unclear, although it has the potential to interact with various downstream molecules. One such downstream target is the lipid kinase phosphatidylinositol 3-kinase (PI 3-kinase), which has been found to bind to activated pp60src and receptor-tyrosine kinases. In this study, we verified that PI 3-kinase associates with the CD4:p56lck complex as judged by the presence of PI 3-phosphate generated from anti-CD4 immunoprecipitates and detected by high-pressure liquid chromatographic analysis. However, surprisingly, CD4-p56lck was also found to associate with another lipid kinase, phosphatidylinositol 4-kinase (PI 4-kinase). The level of associated PI 4-kinase was generally higher than PI 3-kinase activity. HIV-1 gp120 and antibody-mediated cross-linking induced a 5- to 10-fold increase in the level of CD4-associated PI 4- and PI 3-kinases. The use of glutathione S-transferase fusion proteins carrying Lck-SH2, Lck-SH3, and Lck-SH2/SH3 domains showed PI 3-kinase binding to the SH3 domain of p56lck, an interaction facilitated by the presence of an adjacent SH2 domain. PI 4-kinase bound to neither the SH2 nor the SH3 domain of p56lck. CD4-p56lck contributes PI 3- and PI 4-kinase to the activation process of T cells and may play a role in HIV-1-induced immune defects.

scholarly journals Leukocyte-associated immunoglobulin-like receptor 1 inhibits T-cell signaling by decreasing protein phosphorylation in the T-cell signaling pathway

2020 ◽  
Vol 295 (8) ◽  
pp. 2239-2247 ◽  
Author(s):  
Jeoung-Eun Park ◽  
David D. Brand ◽  
Edward F. Rosloniec ◽  
Ae-Kyung Yi ◽  
John M. Stuart ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Cell Signaling ◽  
Signaling Pathway ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Cell Signaling Pathway

Multiple observations implicate T-cell dysregulation as a central event in the pathogenesis of rheumatoid arthritis. Here, we investigated mechanisms for suppressing T-cell activation via the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1). To determine how LAIR-1 affects T-cell receptor (TCR) signaling, we compared 1) T cells from LAIR-1–sufficient and –deficient mice, 2) Jurkat cells expressing either LAIR-1 mutants or C-terminal Src kinase (CSK) mutants, and 3) T cells from mice that contain a CSK transgene susceptible to chemical inhibition. Our results indicated that LAIR-1 engagement by collagen or by complement C1q (C1Q, which contains a collagen-like domain) inhibits TCR signaling by decreasing the phosphorylation of key components in the canonical T-cell signaling pathway, including LCK proto-oncogene SRC family tyrosine kinase (LCK), LYN proto-oncogene SRC family tyrosine kinase (LYN), ζ chain of T-cell receptor–associated protein kinase 70 (ZAP-70), and three mitogen-activated protein kinases (extracellular signal–regulated kinase, c-Jun N-terminal kinase 1/2, and p38). The intracellular region of LAIR-1 contains two immunoreceptor tyrosine-based inhibition motifs that are both phosphorylated by LAIR-1 activation, and immunoprecipitation experiments revealed that Tyr-251 in LAIR-1 binds CSK. Using CRISPR/Cas9-mediated genome editing, we demonstrate that CSK is essential for the LAIR-1–induced inhibition of the human TCR signal transduction. T cells from mice that expressed a PP1 analog–sensitive form of CSK (CskAS) corroborated these findings, and we also found that Tyr-251 is critical for LAIR-1's inhibitory function. We propose that LAIR-1 activation may be a strategy for controlling inflammation and may offer a potential therapeutic approach for managing autoimmune diseases.

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.

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