Gaining Insights into the Ontogeny and Activation of T Cells Through the Use of Gene-Targeted Mutant Mice

1996 ◽  
pp. 129-137
Author(s):  
Tak W. Mak
Keyword(s):  
T Cells ◽  
Mutant Mice

Insights into the ontogeny and activation of T cells

1994 ◽  
Vol 40 (11) ◽  
pp. 2128-2131 ◽  
Author(s):  
T W Mak
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Surface ◽  
Immune Responses ◽  
Tyrosine Phosphatase ◽  
T Cell Development ◽  
Cell Development ◽  
Mutant Mice ◽  
Target Cells

Abstract T lymphocytes recognize antigen peptides and major histocompatibility complex products through their T-cell antigen receptors (TcR), consisting of alpha and beta chains. The interaction between T cells and their target cells or antigen-presenting cells is also assisted by a series of other cell-surface polypeptides, most notably CD4 and CD8, which are selectively expressed on mature helper/inducer and killer/suppressor T cells, respectively. Upon engagement of their ligands, a series of signals is transduced intracytoplasmically via some of these molecules and their associated proteins. Perhaps the most important enzyme in this signal transduction process is the lymphocyte-specific tyrosine kinase lck. Another important component is the cell-surface tyrosine phosphatase CD45. This molecule is alternatively spliced and the different isoforms are expressed on the various hematopoietic and lymphopoietic cells. Signaling through the TcR-CD4 D8-lck-CD45 complex is thought to be insufficient to activate T lymphocytes. A costimulatory signal is believed to be essential, and many investigators have suggested that CD28, a ligand for B7/BB1, is such a signal. Immune responses are also controlled by a number of cytokines and soluble factors. Signaling through the tumor necrosis factor receptor p55 is required for clearance of intracellular pathogens. Transcriptional factors involved in controlling interferon production are also important in T-cell development and immune responses. In an attempt to gain a better understanding of the roles of these molecules in T-lymphocyte functions and ontogeny, we generated a series of mutant mice with disruptions in the genes coding for these molecules. We are analyzing the mutant mice to evaluate the importance of these genes in T-cell development.

scholarly journals A Novel Gene Essential for the Development of Single Positive Thymocytes

2009 ◽  
Vol 29 (18) ◽  
pp. 5128-5135 ◽  
Author(s):  
Kiyokazu Kakugawa ◽  
Takuwa Yasuda ◽  
Ikuo Miura ◽  
Ayako Kobayashi ◽  
Hitomi Fukiage ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mutant Mice ◽  
Cell Phenotype ◽  
Double Positive ◽  
Cell Stage ◽  
Class I Mhc ◽  
Orphan Gene ◽  
Novel Gene ◽  
Single Positive

ABSTRACT A critical step during intrathymic T-cell development is the transition of CD4+ CD8+ double-positive (DP) cells to the major histocompatibility complex class I (MHC-I)-restricted CD4− CD8+ and MHC-II-restricted CD4+ CD8− single-positive (SP) cell stage. Here, we identify a novel gene that is essential for this process. Through the T-cell phenotype-based screening of N-ethyl-N-nitrosourea (ENU)-induced mutant mice, we established a mouse line in which numbers of CD4 and CD8 SP thymocytes as well as peripheral CD4 and CD8 T cells were dramatically reduced. Using linkage analysis and DNA sequencing, we identified a missense point mutation in a gene, E430004N04Rik (also known as themis), that does not belong to any known gene family. This orphan gene is expressed specifically in DP and SP thymocytes and peripheral T cells, whereas in mutant thymocytes the levels of protein encoded by this gene were drastically reduced. We generated E430004N04Rik-deficient mice, and their phenotype was virtually identical to that of the ENU mutant mice, thereby confirming that this gene is essential for the development of SP thymocytes.

Rejection of grafts with no H-2 disparity in TAP1 mutant mice: CD4 T cells are important effector cells and self H-2b class I molecules are target

2002 ◽  
Vol 9 (2-4) ◽  
pp. 101-110 ◽  
Author(s):  
Idania Marrero Suárez ◽  
Luiz Alberto Benvenutti ◽  
Irene Noronha ◽  
Luc Van Kaer ◽  
Jorge Kalil ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Mutant Mice ◽  
Class I ◽  
Effector Cells

Impaired germinal center formation and recall T-cell–dependent immune responses in mice lacking the costimulatory ligand B7-H2

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1381-1388 ◽  
Author(s):  
Siew-Cheng Wong ◽  
Edwin Oh ◽  
Chee-Hoe Ng ◽  
Kong-Peng Lam
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
Heavy Chain ◽  
Germinal Center ◽  
Critical Role ◽  
Mutant Mice ◽  
Type Ii ◽  
Germinal Center Formation

Abstract B7-H2, which is expressed constitutively on B cells and binds the inducible costimulator (ICOS) on antigen-activated T cells, is a member of the B7 family of costimulatory ligands. We have inactivated B7-H2 in the mouse. B7-H2–/– mice generate normal populations of B and T cells in their various lymphoid organs but have lower basal levels of heavy chain class–switched antibodies in their sera. These mice are able to mount normal immune responses to both type I and type II T-cell–independent antigens. However, their pattern of responses to a T-cell–dependent antigen is altered, with greatly reduced production of antigen-specific heavy chain class–switched antibodies, the levels of which could not be elevated even with repeated immunizations. This suggests a critical role for B7-H2 in the recall phases of the immune response. Germinal center formation is also impaired in the mutant mice. While B cells from the mutant mice could response normally to anti-IgM, anti-CD40, and lipopolysaccharide stimulation, the production of T-helper–type II cytokines such as interleukin-4 (IL-4) and IL-10 by primed CD4+ T cells from mutant mice were reduced. This indicated that the defects in humoral responses and germinal center formation in B7-H2–deficient mice are due to the lack of T-cell–mediated help to the B cells. Hence, B7-H2 on B cells is important for recruiting T-cell help via its interaction with ICOS and plays a critical role in costimulating humoral immune responses.

scholarly journals Th2 Lymphoproliferative Disorder of LatY136F Mutant Mice Unfolds Independently of TCR-MHC Engagement and Is Insensitive to the Action of Foxp3+ Regulatory T Cells

2008 ◽  
Vol 180 (3) ◽  
pp. 1565-1575 ◽  
Author(s):  
Ying Wang ◽  
Adrien Kissenpfennig ◽  
Michael Mingueneau ◽  
Sylvie Richelme ◽  
Pierre Perrin ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Lymphoproliferative Disorder ◽  
Mutant Mice

scholarly journals Eosinophilia, IgE production, and cytokine production by lung T cells in surface CD4‐deficient mutant mice infected with Toxocara canis

Immunology ◽  
1998 ◽  
Vol 95 (1) ◽  
pp. 97-104 ◽  
Author(s):  
TAKAMOTO ◽  
WANG ◽  
WATANABE ◽  
MATSUZAWA ◽  
NARIUCHI ◽  
...  
Keyword(s):  
T Cells ◽  
Cytokine Production ◽  
Toxocara Canis ◽  
Mutant Mice ◽  
Deficient Mutant

Abstract 1211: Hif-1α In T Cells Pathway Plays A Crucial Role In The Progression Of Arteriosclerosis And Artery Intimal Thickening

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hirotsugu Kurobe ◽  
Masahisa Urata ◽  
Yuki Izawa ◽  
Yayoi Fukuhara ◽  
Tamotsu Kanbara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Crucial Role ◽  
Vascular Remodeling ◽  
Mononuclear Cells ◽  
Negative Regulator ◽  
Mutant Mice ◽  
Gene Expressions ◽  
Deficient Mice

Background and Objective T cell-mediated inflammatory process is involved in arteriosclerosis and vascular remodeling. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor and regulates the gene expressions in response to hypoxia in order to maintain physiological oxygen homeostasis. In the previous annual meeting, we showed that arterial cuff injury caused prominent neointimal and adventitial hyperplasia in Hif-1α-deficient mice compared to that of the control mice. The object of the present study is to reveal how the function of HIF-1α in T cells contributes to the vascular remodeling. Methods and Results T cell-specific Hif-1α-deficient mice were generated using a Cre-LoxP technology. Vascular remodeling was characterized 4 weeks after femoral arterial injury induced by an external vascular polyethylene cuff model. Morphological and histological studies showed that the cuff placement caused prominent neointimal and adventitial hyperplasia in Hif-1α-deficient mice compared to that of the control mice, and that infiltration of mononuclear cells at the adventitia was remarkably increased in the mutant mice. Hif-1α-deficient T cells were normally generated in the thymus and their distribution in the spleen and lymph nodes was unimpaired. However, number of peripheral Hif-1α-deficient T cells was significantly increased compared to the control. In the in vitro culture condition, Hif-1α-deficient T cells exhibited significant more increases of IL2 production and proliferation upon stimulation with anti-CD3/anti-CD28 antibodies compared to the controls. In addition, productions of 2,4,6-trinitrophenol (TNP)-KLH antigen-specific antibodies, including IgG1, IgG2b and IgG2c, were more enhanced in the mutant mice after stimulation of the antigen. Conclusions HIF-1α in T cells plays a crucial role in vascular inflammation and remodeling in response to cuff injury, serving as a negative regulator of T cell-mediated immune response.

scholarly journals Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7–dependent homeostatic proliferation of CD4+ T cells

2006 ◽  
Vol 203 (6) ◽  
pp. 1459-1470 ◽  
Author(s):  
Shin-ichiro Sawa ◽  
Daisuke Kamimura ◽  
Gui-Hua Jin ◽  
Hideyuki Morikawa ◽  
Hokuto Kamon ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Conditional Knockout ◽  
Mutant Mice ◽  
Joint Disease ◽  
Homeostatic Proliferation ◽  
Antibody Treatment ◽  
Mhc Ii ◽  
Stat3 Signaling ◽  
Enhanced Production

Mice homozygous for the F759 mutation in the gp130 interleukin (IL)-6 receptor subunit have enhanced gp130-mediated signal transducer and activator of transcription (STAT)3 activation and spontaneously developed a lymphocyte-mediated rheumatoid arthritis-like joint disease. Here, we show that the development of the disease is dependent on both major histocompatibility complex (MHC) II–restricted CD4+ T cells and IL-6 family cytokines. In spite of the necessity for CD4+ T cells, the gp130 mutation was only required in nonhemtopoietic cells for the disease. The gp130 mutation resulted in enhanced production of IL-7. Conditional knockout of STAT3 in nonlymphoid cells showed that the enhancement of IL-7 production was dependent on STAT3 activation by IL-6 family cytokines. Homeostatic proliferation of CD4+ T cells was enhanced in gp130 mutant mice and acceleration of homeostatic proliferation enhanced the disease, whereas the inhibition of homeostatic proliferation suppressed the disease. Anti–IL-7 antibody treatment inhibited not only the enhanced homeostatic proliferation, but also the disease in gp130 mutant mice. Thus, our results show that autoimmune disease in gp130 mutant mice is caused by increased homeostatic proliferation of CD4+ T cells, which is due to elevated production of IL-7 by nonhematopoietic cells as a result of IL-6 family cytokine-gp130-STAT3 signaling.

scholarly journals Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis

2007 ◽  
Vol 204 (12) ◽  
pp. 2875-2888 ◽  
Author(s):  
Ichiro Onoyama ◽  
Ryosuke Tsunematsu ◽  
Akinobu Matsumoto ◽  
Taichi Kimura ◽  
Ignacio Moreno de Alborán ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Cell Lineage ◽  
Mutant Mice ◽  
Dependent Manner ◽  
Protein Subunit ◽  
Ubiquitin Ligase Complex ◽  
Conditional Inactivation ◽  
F Box Protein

Cell proliferation is strictly controlled during differentiation. In T cell development, the cell cycle is normally arrested at the CD4+CD8+ stage, but the mechanism underlying such differentiation-specific exit from the cell cycle has been unclear. Fbxw7 (also known as Fbw7, Sel-10, hCdc4, or hAgo), an F-box protein subunit of an SCF-type ubiquitin ligase complex, induces the degradation of positive regulators of the cell cycle, such as c-Myc, c-Jun, cyclin E, and Notch. FBXW7 is often mutated in a subset of human cancers. We have now achieved conditional inactivation of Fbxw7 in the T cell lineage of mice and found that the cell cycle is not arrested at the CD4+CD8+ stage in the homozygous mutant animals. The mutant mice manifested thymic hyperplasia as a result of c-Myc accumulation and eventually developed thymic lymphoma. In contrast, mature T cells of the mutant mice failed to proliferate in response to mitogenic stimulation and underwent apoptosis in association with accumulation of c-Myc and p53. These latter abnormalities were corrected by deletion of p53. Our results suggest that Fbxw7 regulates the cell cycle in a differentiation-dependent manner, with its loss resulting in c-Myc accumulation that leads to hyperproliferation in immature T cells but to p53-dependent cell-cycle arrest and apoptosis in mature T cells.

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