scholarly journals Histone methyltransferase Nsd2 is required for follicular helper T cell differentiation

2019 ◽  
Vol 217 (1) ◽  
Author(s):  
Xuehui Long ◽  
Le Zhang ◽  
Yang Zhang ◽  
Min Min ◽  
Bichun Lin ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Dependent Manner ◽  
Humoral Immune ◽  
Follicular Helper ◽  
Virus Clearance ◽  
Follicular Helper T Cell ◽  
Early Expression ◽  
Bcl6 Expression

Follicular helper T (Tfh) cells provide essential help for humoral immune response. Transcriptional factor Bcl6 is the master regulator for Tfh generation and is induced very early after T cell activation in a CD28-dependent manner, but how CD28 signal promotes Bcl6 early expression remains unknown. Here we found that CD28 signal quickly induces expression of the H3K36me2 methytransferase Nsd2, which is required for Bcl6 expression as early as the first cell division after T cell activation. Nsd2 deficiency in T cells leads to decreased Bcl6 expression, impaired Tfh generation, compromised germinal center response, and delayed virus clearance. Ectopic Bcl6 expression rescues the Tfh defect of Nsd2 KO cells. ICOS signal is dispensable for early Nsd2 induction but required for sustained Nsd2 expression, which is critical for Tfh maintenance. Overexpression of Nsd2 increases Bcl6 expression and enhances Tfh generation; 4-mo-old mice even develop spontaneous Tfh. Overall, our study reveals Nsd2 as a critical epigenetic regulator for Tfh differentiation.

scholarly journals CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

2014 ◽  
Vol 112 (2) ◽  
pp. 524-529 ◽  
Author(s):  
Chun Jing Wang ◽  
Frank Heuts ◽  
Vitalijs Ovcinnikovs ◽  
Lukasz Wardzinski ◽  
Chantelle Bowers ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Responses ◽  
Dependent Manner ◽  
Cell Responses ◽  
Follicular Helper ◽  
Follicular Helper T Cell

Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an essential regulator of T-cell responses, and its absence precipitates lethal T-cell hyperactivity. However, whether CTLA-4 acts simply to veto the activation of certain clones or plays a more nuanced role in shaping the quality of T-cell responses is not clear. Here we report that T cells in CTLA-4–deficient mice show spontaneous T-follicular helper (TFH) differentiation in vivo, and this is accompanied by the appearance of large germinal centers (GCs). Remarkably, short-term blockade with anti–CTLA-4 antibody in wild-type mice is sufficient to elicit TFH generation and GC development. The latter occurs in a CD28-dependent manner, consistent with the known role of CTLA-4 in regulating the CD28 pathway. CTLA-4 can act by down-regulating CD80 and CD86 on antigen presenting cells (APCs), thereby altering the level of CD28 engagement. To mimic reduced CD28 ligation, we used mice heterozygous for CD28, revealing that the magnitude of CD28 engagement is tightly linked to the propensity for TFH differentiation. In contrast, other parameters of T-cell activation, including CD62L down-regulation and Ki67 expression, were relatively insensitive to altered CD28 level. Altered TFH generation as a result of graded reduction in CD28 was associated with decreased numbers of GC B cells and a reduction in overall GC size. These data support a model in which CTLA-4 control of immunity goes beyond vetoing T-cell priming and encompasses the regulation of TFH differentiation by graded control of CD28 engagement.

scholarly journals CRL4-DCAF12 Ubiquitin Ligase Controls MOV10 RNA Helicase during Spermatogenesis and T Cell Activation

2021 ◽  
Vol 22 (10) ◽  
pp. 5394
Author(s):  
Tomas Lidak ◽  
Nikol Baloghova ◽  
Vladimir Korinek ◽  
Radislav Sedlacek ◽  
Jana Balounova ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Ubiquitin Ligase ◽  
Cell Activation ◽  
Rna Helicase ◽  
Dependent Manner ◽  
Amino Acid Residues ◽  
Risc Complex ◽  
Wide Range

Multisubunit cullin-RING ubiquitin ligase 4 (CRL4)-DCAF12 recognizes the C-terminal degron containing acidic amino acid residues. However, its physiological roles and substrates are largely unknown. Purification of CRL4-DCAF12 complexes revealed a wide range of potential substrates, including MOV10, an “ancient” RNA-induced silencing complex (RISC) complex RNA helicase. We show that DCAF12 controls the MOV10 protein level via its C-terminal motif in a proteasome- and CRL-dependent manner. Next, we generated Dcaf12 knockout mice and demonstrated that the DCAF12-mediated degradation of MOV10 is conserved in mice and humans. Detailed analysis of Dcaf12-deficient mice revealed that their testes produce fewer mature sperms, phenotype accompanied by elevated MOV10 and imbalance in meiotic markers SCP3 and γ-H2AX. Additionally, the percentages of splenic CD4+ T and natural killer T (NKT) cell populations were significantly altered. In vitro, activated Dcaf12-deficient T cells displayed inappropriately stabilized MOV10 and increased levels of activated caspases. In summary, we identified MOV10 as a novel substrate of CRL4-DCAF12 and demonstrated the biological relevance of the DCAF12-MOV10 pathway in spermatogenesis and T cell activation.

scholarly journals Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function in sleep apnoea

2017 ◽  
Vol 50 (4) ◽  
pp. 1700833 ◽  
Author(s):  
Carolina Cubillos-Zapata ◽  
Jose Avendaño-Ortiz ◽  
Enrique Hernandez-Jimenez ◽  
Victor Toledano ◽  
Jose Casas-Martin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Intermittent Hypoxia ◽  
Cell Activation ◽  
Cell Function ◽  
Sleep Apnoea ◽  
Orphan Receptor ◽  
Dependent Manner ◽  
Obstructive Sleep

Obstructive sleep apnoea (OSA) is associated with higher cancer incidence, tumour aggressiveness and cancer mortality, as well as greater severity of infections, which have been attributed to an immune deregulation. We studied the expression of programmed cell death (PD)-1 receptor and its ligand (PD-L1) on immune cells from patients with OSA, and its consequences on immune-suppressing activity. We report that PD-L1 was overexpressed on monocytes and PD-1 was overexpressed on CD8+ T-cells in a severity-dependent manner. PD-L1 and PD-1 overexpression were induced in both the human in vitro and murine models of intermittent hypoxia, as well as by hypoxia-inducible factor-1α transfection. PD-L1/PD-1 crosstalk suppressed T-cell proliferation and activation of autologous T-lymphocytes and impaired the cytotoxic activity of CD8+ T-cells. In addition, monocytes from patients with OSA exhibited high levels of retinoic acid related orphan receptor, which might explain the differentiation of myeloid-derived suppressor cells. Intermittent hypoxia upregulated the PD-L1/PD-1 crosstalk in patients with OSA, resulting in a reduction in CD8+ T-cell activation and cytotoxicity, providing biological plausibility to the increased incidence and aggressiveness of cancer and the higher risk of infections described in these patients.

scholarly journals Human T cell activation. IV. T cell activation and proliferation via the early activation antigen EA 1.

1989 ◽  
Vol 169 (3) ◽  
pp. 677-689 ◽  
Author(s):  
S Nakamura ◽  
S S Sung ◽  
J M Bjorndahl ◽  
S M Fu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Early Activation ◽  
Human T Cell ◽  
Accessory Cells ◽  
Activation Antigen

A new mAb G38 was generated against purified EA 1, an early activation antigen. In immunoprecipitation, it was reactive with the same complex precipitated by the initial anti-EA 1 mAb P8. mAb G38 augmented PMA-induced proliferation of PBMC. It was shown to be mitogenic for purified T cells in collaboration with PMA in a dose-dependent manner. This effect was independent of monocytes and other accessory cells. mAb G38 augmented PMA-induced IL-2-R expression. In conjunction with PMA, it induced IL-2 synthesis and secretion. Its effects on IL-2-R and IL-2 expression were documented at both protein and mRNA levels. Both anti-EA 1 mAbs did not induce Ca2+ influx by themselves in PMA-treated T cells. However, the addition of second anti-mouse Ig antibodies induced readily detectable increases in [Ca2+]i. Ca2+-mediated pathways may be utilized as the transduction signal mechanisms. mAb Leu-23 was shown to be reactive with EA 1. mAb Leu-23 was also mitogenic for T cells in the presence of PMA. These findings provide evidence for a functional role for EA 1 in T cell activation and proliferation.

scholarly journals PPARγ Negatively Regulates T Cell Activation to Prevent Follicular Helper T Cells and Germinal Center Formation

PLoS ONE ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. e99127 ◽  
Author(s):  
Hong-Jai Park ◽  
Do-Hyun Kim ◽  
Jin-Young Choi ◽  
Won-Ju Kim ◽  
Ji Yun Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Germinal Center ◽  
Cell Activation ◽  
Helper T Cells ◽  
Follicular Helper T Cells ◽  
Follicular Helper ◽  
Germinal Center Formation

scholarly journals Gastric Helicobacter Infection Inhibits Development of Oral Tolerance to Food Antigens in Mice

2003 ◽  
Vol 71 (9) ◽  
pp. 5219-5224 ◽  
Author(s):  
Tamara Matysiak-Budnik ◽  
Guillaume van Niel ◽  
Francis Mégraud ◽  
Kathryn Mayo ◽  
Claudia Bevilacqua ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Oral Tolerance ◽  
Cell Activation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Protective Agent ◽  
Dependent Manner ◽  
Food Antigens

ABSTRACT The increase in the transcellular passage of intact antigens across the digestive epithelium infected with Helicobacter pylori may interfere with the regulation of mucosal immune responses. The aim of this work was to study the capacity of Helicobacter infection to inhibit the development of oral tolerance or to promote allergic sensitization and the capacity of a gastro-protective agent, rebamipide, to interfere with these processes in mice. Oral tolerance to ovalbumin (OVA) was studied in 48 C3H/He 4-week-old mice divided into four groups: (i) OVA-sensitized mice; (ii) OVA-“tolerized” mice (that is, mice that were rendered immunologically tolerant); (iii) H. felis-infected, OVA-tolerized mice; (iv) and H. felis-infected, OVA-tolerized, rebamipide-treated mice. Oral sensitization to hen egg lysozyme (HEL) was studied in 48 mice divided into four groups: (i) controls; (ii) HEL-sensitized mice; (iii) H. felis-infected, HEL-sensitized mice; and (iv) H. felis-infected, HEL-sensitized, rebamipide-treated mice. Specific anti-OVA or anti-HEL immunoglobulin E (IgE) and IgG1/IgG2a serum titers were measured by enzyme-linked immunosorbent assay. Additionally, the capacity of rebamipide to interfere with antigen presentation and T-cell activation in vitro, as well as absorption of rebamipide across the epithelial monolayer, was tested. H. felis infection led to the inhibition of oral tolerance to OVA, but rebamipide prevented this inhibitive effect of H. felis. H. felis infection did not enhance the sensitization to HEL, but rebamipide inhibited the development of this sensitization. Moreover, rebamipide inhibited in a dose-dependent manner antigen presentation and T-cell activation in vitro and was shown to be able to cross the epithelium at a concentration capable of inducing this inhibitory effect. We conclude that H. felis can inhibit the development of oral tolerance to OVA in mice and that this inhibition is prevented by rebamipide.

scholarly journals The NFAT-Related Protein NFATL1 (TonEBP/NFAT5) Is Induced Upon T Cell Activation in a Calcineurin-Dependent Manner

2000 ◽  
Vol 165 (9) ◽  
pp. 4884-4894 ◽  
Author(s):  
Jason Trama ◽  
Qingjun Lu ◽  
Robert G. Hawley ◽  
Steffan N. Ho
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Dependent Manner ◽  
Related Protein

scholarly journals NSOM/QD-Based Visualization of GM1 Serving as Platforms for TCR/CD3 Mediated T-Cell Activation

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Liyun Zhong ◽  
Zhun Zhang ◽  
Xiaoxu Lu ◽  
Shengde Liu ◽  
Crystal Y. Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Imaging System ◽  
Near Field ◽  
Cell Receptor ◽  
Dependent Manner ◽  
Receptor Complexes ◽  
Before And After

Direct molecular imaging of nanoscale relationship between T-cell receptor complexes (TCR/CD3) and gangliosidosis GM1 before and after T-cell activation has not been reported. In this study, we made use of our expertise of near-field scanning optical microscopy(NSOM)/immune-labeling quantum dots- (QD-)based dual-color imaging system to visualize nanoscale profiles for distribution and organization of TCR/CD3, GM1, as well as their nanospatial relationship and their correlation with PKCθsignaling cascade during T-cell activation. Interestingly, after anti-CD3/anti-CD28 Ab co-stimulation, both TCR/CD3 and GM1 were clustered to form nanodomains; moreover, all of TCR/CD3 nanodomains were colocalized with GM1 nanodomains, indicating that the formation of GM1 nanodomains was greatly correlated with TCR/CD3 mediated signaling. Specially, while T-cells were pretreated with PKCθsignaling inhibitor rottlerin to suppress IL-2 cytokine production, no visible TCR/CD3 nanodomains appeared while a lot of GM1 nanodomains were still observed. However, while T-cells are pretreated with PKCαβsignaling inhibitor GÖ6976 to suppress calcium-dependent manner, all of TCR/CD3 nanodomains were still colocalized with GM1 nanodomains. These findings possibly support the notion that the formation of GM1 nanodomains indeed serves as platforms for the recruitment of TCR/CD3 nanodomains, and TCR/CD3 nanodomains are required for PKCθsignaling cascades and T-cell activation

scholarly journals Differential Regulation of TCR-mediated Gene Transcription by Vav Family Members

2004 ◽  
Vol 199 (3) ◽  
pp. 429-434 ◽  
Author(s):  
Shaheen Zakaria ◽  
Timothy S. Gomez ◽  
Doris N. Savoy ◽  
Simon McAdam ◽  
Martin Turner ◽  
...  
Keyword(s):  
T Cell ◽  
Gene Transcription ◽  
T Cell Activation ◽  
Cell Activation ◽  
Family Members ◽  
Cell Receptor ◽  
Differential Regulation ◽  
Dependent Manner ◽  
Cross Linkage ◽  
Serum Response

Although all three Vav family members are expressed in T lymphocytes, the role that Vav3 plays in T cell activation is poorly defined. Here we show that, like Vav1, Vav3 undergoes rapid tyrosine phosphorylation after T cell receptor (TCR) cross-linkage and interacts with the adaptor molecules SLP76 and 3BP2 in a SH2-dependent manner. However, depletion of Vav1 but not Vav3 protein by RNA interference affects TCR-mediated IL-2 promoter activity. In contrast, Vav3 function is specifically required for coupling TCR stimulation to serum response element–mediated gene transcription. These data indicate that, although both Vav proteins are biochemically coupled to the TCR, they regulate distinct molecular pathways leading to defined gene transcriptional events.

Sign in / Sign up

Export Citation Format

Share Document