scholarly journals Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner

2020 ◽  
Vol 21 (18) ◽  
pp. 6965 ◽  
Author(s):  
Tiago Carvalheiro ◽  
Carlos Rafael-Vidal ◽  
Beatriz Malvar-Fernandez ◽  
Ana P. Lopes ◽  
Jose M. Pego-Reigosa ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Neutralizing Antibody ◽  
Negative Regulator ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Th17 Differentiation

Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4+ T cell activation induces the expression of Sema4A. However, the autocrine role of Sema4A on Th cell differentiation remains unknown. Naïve Th cells from healthy controls were cell sorted and differentiated into Th1, Th2 and Th17 in the presence or absence of a neutralizing antibody against the Sema4A receptor PlexinD1. Gene expression was determined by quantitative PCR and protein expression by ELISA and flow cytometry. We found that the expression of Sema4A is induced during Th1, Th2 and Th17 differentiation. PlexinD1 neutralization induced the differentiation of Th1 cells, while reduced the Th2 and Th17 skewing. These effects were associated with an upregulation of the transcription factor T-bet by Th1 cells, and to downregulation of GATA3 and RORγt in Th2 cells and Th17 cells, respectively. Finally, PlexinD1 neutralization regulates the systemic sclerosis patients serum-induced cytokine production by CD4+ T cells. Therefore, the autocrine Sema4A-PlexinD1 signaling acts as a negative regulator of Th1 skewing but is a key mediator on Th2 and Th17 differentiation, suggesting that dysregulation of this axis might be implicated in the pathogenesis of CD4+ T cell-mediated diseases.

scholarly journals ROG Negatively Regulates T-Cell Activation but Is Dispensable for Th-Cell Differentiation

2005 ◽  
Vol 25 (2) ◽  
pp. 554-562 ◽  
Author(s):  
Bok Yun Kang ◽  
Shi-Chuen Miaw ◽  
I-Cheng Ho
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Target Gene ◽  
Interleukin 2 ◽  
Negative Regulator ◽  
Th2 Cells ◽  
Th Cells ◽  
And Function

ABSTRACT ROG, a transcriptional repressor, is a direct target gene of NF-AT and a putative negative regulator of T-cell activation. In addition, overexpression of ROG suppresses the activity of GATA-3, implying a role of ROG in the differentiation and function of Th cells. Despite these observations, the function of ROG has yet to be confirmed by loss-of-function approaches. Here we report that ROG-deficient T cells are hypersensitive to anti-CD3 stimulation and produce more interleukin-2 (IL-2) due to enhanced NF-κB activity. ROG-deficient dendritic cells also produce more IL-12p40, another NF-κB target gene. However, ROG-deficient Th cells are capable of differentiating into Th1 and Th2 cells, and ROG-deficient mice have no defect in mounting appropriate Th immune responses in vivo. Thus, ROG is dispensable for the differentiation and function of Th cells but serves as a mediator of NF-AT-initiated suppression of NF-κB. Its mechanism of action and its expression pattern are distinct from those of other transcription factors negatively regulating the activation of T cells.

scholarly journals Cord-Blood-Derived Mesenchymal Stromal Cells Downmodulate CD4+ T-Cell Activation by Inducing IL-10-Producing Th1 Cells

2013 ◽  
Vol 22 (7) ◽  
pp. 1063-1075 ◽  
Author(s):  
Silvia Selleri ◽  
Mame Massar Dieng ◽  
Simon Nicoletti ◽  
Isabelle Louis ◽  
Christian Beausejour ◽  
...  
Keyword(s):  
T Cell ◽  
Cord Blood ◽  
Mesenchymal Stromal Cells ◽  
T Cell Activation ◽  
Stromal Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Th1 Cells

scholarly journals GTPase-activating protein Rasal1 associates with ZAP-70 of the TCR and negatively regulates T-cell tumor immunity

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Youg Raj Thaker ◽  
Monika Raab ◽  
Klaus Strebhardt ◽  
Christopher E. Rudd
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Negative Regulator ◽  
Cd4 T Cell ◽  
Gtpase Activating Protein ◽  
Cell Responses

Abstract Immunotherapy involving checkpoint blockades of inhibitory co-receptors is effective in combating cancer. Despite this, the full range of mediators that inhibit T-cell activation and influence anti-tumor immunity is unclear. Here, we identify the GTPase-activating protein (GAP) Rasal1 as a novel TCR-ZAP-70 binding protein that negatively regulates T-cell activation and tumor immunity. Rasal1 inhibits via two pathways, the binding and inhibition of the kinase domain of ZAP-70, and GAP inhibition of the p21ras-ERK pathway. It is expressed in activated CD4 + and CD8 + T-cells, and inhibits CD4 + T-cell responses to antigenic peptides presented by dendritic cells as well as CD4 + T-cell responses to peptide antigens in vivo. Furthermore, siRNA reduction of Rasal1 expression in T-cells shrinks B16 melanoma and EL-4 lymphoma tumors, concurrent with an increase in CD8 + tumor-infiltrating T-cells expressing granzyme B and interferon γ-1. Our findings identify ZAP-70-associated Rasal1 as a new negative regulator of T-cell activation and tumor immunity.

scholarly journals The focal adhesion kinase inhibitor PF-562,271 impairs primary CD4+ T cell activation

2013 ◽  
Vol 86 (6) ◽  
pp. 770-781 ◽  
Author(s):  
Andrew J. Wiemer ◽  
Sarah A. Wernimont ◽  
Thai-duong Cung ◽  
David A. Bennin ◽  
Hilary E. Beggs ◽  
...  
Keyword(s):  
T Cell ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
T Cell Activation ◽  
Cell Activation ◽  
Kinase Inhibitor ◽  
Cd4 T Cell

scholarly journals Resveratrol Inhibits CD4+ T Cell Activation by Enhancing the Expression and Activity of Sirt1

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e75139 ◽  
Author(s):  
Ting Zou ◽  
Yi Yang ◽  
Fei Xia ◽  
Anfei Huang ◽  
Xiaoming Gao ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Expression And Activity
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