scholarly journals Cooperative Interaction of Nck and Lck Orchestrates Optimal TCR Signaling

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 834
Author(s):  
Frederike A. Hartl ◽  
Jatuporn Ngoenkam ◽  
Esmeralda Beck-Garcia ◽  
Liz Cerqueira ◽  
Piyamaporn Wipa ◽  
...  
Keyword(s):  
T Cell ◽  
Ligand Binding ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptor Protein ◽  
Cooperative Interaction ◽  
Tcr Signaling ◽  
Binding Motifs ◽  
Adaptive Immune

The T cell antigen receptor (TCR) is expressed on T cells, which orchestrate adaptive immune responses. It is composed of the ligand-binding clonotypic TCRαβ heterodimer and the non-covalently bound invariant signal-transducing CD3 complex. Among the CD3 subunits, the CD3ε cytoplasmic tail contains binding motifs for the Src family kinase, Lck, and the adaptor protein, Nck. Lck binds to a receptor kinase (RK) motif and Nck binds to a proline-rich sequence (PRS). Both motifs only become accessible upon ligand binding to the TCR and facilitate the recruitment of Lck and Nck independently of phosphorylation of the TCR. Mutations in each of these motifs cause defects in TCR signaling and T cell activation. Here, we investigated the role of Nck in proximal TCR signaling by silencing both Nck isoforms, Nck1 and Nck2. In the absence of Nck, TCR phosphorylation, ZAP70 recruitment, and ZAP70 phosphorylation was impaired. Mechanistically, this is explained by loss of Lck recruitment to the stimulated TCR in cells lacking Nck. Hence, our data uncover a previously unknown cooperative interaction between Lck and Nck to promote optimal TCR signaling.

scholarly journals Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor

2018 ◽  
Author(s):  
O. Sascha Yousefi ◽  
Matthias Günther ◽  
Maximilian Hörner ◽  
Julia Chalupsky ◽  
Maximilian Wess ◽  
...  
Keyword(s):  
T Cell ◽  
Ligand Binding ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Half Life ◽  
Cell Activation ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Experimental Systems ◽  
Kinetic Proofreading

AbstractThe pivotal task of the immune system is to distinguish between self and foreign antigens. The kinetic proofreading model (KPR) proposes that T cells discriminate self from foreign ligands by the different ligand binding half-lives to the T cell receptor (TCR). It is challenging to test KPR as the available experimental systems fall short of only altering the binding half-lives and keeping other parameters of the ligand-TCR interaction unchanged. We engineered an optogenetic system using the plant photoreceptor phytochrome B to selectively control the dynamics of ligand binding to the TCR by light. Combining experiments with mathematical modeling we find that the ligand-TCR interaction half-life is the decisive factor for activating downstream TCR signaling, substantiating the KPR hypothesis.One Sentence SummaryThe half-life of the ligand-T cell receptor complex determines T cell activation.

The actin cloud induced by LFA-1–mediated outside-in signals lowers the threshold for T-cell activation

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 168-175 ◽  
Author(s):  
Jun-ichiro Suzuki ◽  
Sho Yamasaki ◽  
Jennifer Wu ◽  
Gary A. Koretzky ◽  
Takashi Saito
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
Cloud Formation ◽  
Lymphocyte Function ◽  
Tcr Signaling

Abstract The dynamic rearrangement of the actin cytoskeleton plays critical roles in T-cell receptor (TCR) signaling and immunological synapse (IS) formation in T cells. Following actin rearrangement in T cells upon TCR stimulation, we found a unique ring-shaped reorganization of actin called the “actin cloud,” which was specifically induced by outside-in signals through lymphocyte function–associated antigen-1 (LFA-1) engagement. In T-cell–antigen-presenting cell (APC) interactions, the actin cloud is generated in the absence of antigen and localized at the center of the T-cell–APC interface, where it accumulates LFA-1 and tyrosine-phosphorylated proteins. The LFA-1–induced actin cloud formation involves ADAP (adhesion- and degranulation-promoting adaptor protein) phosphorylation, LFA-1/ADAP assembly, and c-Jun N-terminal kinase (JNK) activation, and occurs independent of TCR and its proximal signaling. The formation of the actin cloud lowers the threshold for subsequent T-cell activation. Thus, the actin cloud induced by LFA-1 engagement may serve as a possible platform for LFA-1–mediated costimulatory function for T-cell activation.

Potential role of hypovitaminosis D in renal cell carcinoma patients treated with immune-checkpoint inhibitors.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 50-50
Author(s):  
Melissa Bersanelli ◽  
Augusto Vaglio ◽  
Nicola Sverzellati ◽  
Maricla Galetti ◽  
Monia Incerti ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Potential Role ◽  
Checkpoint Inhibitors ◽  
Hypovitaminosis D ◽  
Tcr Signaling ◽  
Vitamin D Levels

50 Background: hypovitaminosis D is frequent in renal diseases but it was never reported in metastatic renal cell carcinoma (mRCC). The interaction between vitamin D and its receptor (VDR) has a key role for T-cell activation. Naïve T-cells do not express VDR and had very low expression of phospholipase C-γ1 (PLC-γ1), with low responsiveness to T-cell receptor (TCR). Initial TCR signaling induces VDR expression and upregulates PLC-γ1 via the kinase p38 pathway. VDR interaction with high concentrations of vitamin D and PLC-γ1 increase are required to trigger classical TCR signaling, increasing T-cell responsiveness. On these basis, we hypothesized that hypovitaminosis D could contribute to lower responsiveness to immune-checkpoint inhibitors (CKI). Methods: we assessed vitamin D levels of mRCC patients undergoing therapy with CKI, with the aim to reveal hypovitaminosis D, evaluate its prevalence and hypothesize its potential role in the outcome of treatment with CKI. Results: of 10 mRCC patients pretreated with tyrosine-kinase inhibitors, vitamin D levels assessed before the first treatment with nivolumab (anti-PD1 CKI) revealed deficiency in 80% of cases (8 patients). Hypovitaminosis D was severe ( < 20 ng/ml) in 7 cases and moderate ( < 30 ng/ml) in one. The 2 patients without deficiency (20%), had vitamin D values near to the lower limit of normality. Oral supplementation with cholecalciferol was given when necessary, likely confounding the possible influence of vitamin D deficiency on the outcome of CKI treatment. Vitamin D normal values after two months of therapy were recovered in the great majority of cases. Interestingly, the only patient who achieved a good objective response to treatment had normal values of vitamin D before therapy. Conclusions: hypovitaminosis D could have a relevant prevalence in mRCC patients. Considering the role of vitamin D in T-cell activation, assessment of its levels and initiation of a supplementation before immunotherapy should be considered to enhance responsiveness. On the basis of these observations, we are planning a perspective multicenter study to investigate the role of hypovitaminosis D in mRCC patients treated with CKI (PRoviDenCe study).

Inhibition of T cell activation and function by the adaptor protein CIN85

2019 ◽  
Vol 12 (567) ◽  
pp. eaav4373 ◽  
Author(s):  
Mei Suen Kong ◽  
Akiko Hashimoto-Tane ◽  
Yusuke Kawashima ◽  
Machie Sakuma ◽  
Tadashi Yokosuka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
Tcr Signaling ◽  
Signaling Complex

T cell activation is initiated by signaling molecules downstream of the T cell receptor (TCR) that are organized by adaptor proteins. CIN85 (Cbl-interacting protein of 85 kDa) is one such adaptor protein. Here, we showed that CIN85 limited T cell responses to TCR stimulation. Compared to activated wild-type (WT) T cells, those that lacked CIN85 produced more IL-2 and exhibited greater proliferation. After stimulation of WT T cells with their cognate antigen, CIN85 was recruited to the TCR signaling complex. Early TCR signaling events, such as phosphorylation of ζ-chain–associated protein kinase 70 (Zap70), Src homology 2 (SH2) domain–containing leukocyte protein of 76 kDa (SLP76), and extracellular signal–regulated kinase (Erk), were enhanced in CIN85-deficient T cells. The inhibitory function of CIN85 required the SH3 and PR regions of the adaptor, which associated with the phosphatase suppressor of TCR signaling–2 (Sts-2) after TCR stimulation. Together, our data suggest that CIN85 is recruited to the TCR signaling complex and mediates inhibition of T cell activation through its association with Sts-2.

CD2 engagement induces dendritic cell activation: implications for immune surveillance and T-cell activation

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1745-1752 ◽  
Author(s):  
Keith Crawford ◽  
Aleksandra Stark ◽  
Betsy Kitchens ◽  
Kerry Sternheim ◽  
Vassilios Pantazopoulos ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Surveillance ◽  
T Cell Proliferation ◽  
Dendritic Cell Activation ◽  
Adaptive Immune

Abstract We have shown previously that primary dendritic cells and monocytes express equal levels of CD14 but are distinguishable by the presence of CD2 on dendritic cells. CD2 is known to mediate the activation of T and natural killer (NK) cells through its interaction with CD58. CD2 epitopes recognized by anti-T111, -T112, and -T113 monoclonal antibodies (mAbs) are present on dendritic cells. Here we show that CD2 engagement significantly increases class II, costimulatory (CD40, CD80, CD86), adhesion (CD54, CD58), and CCR7 molecule expression on primary dendritic cells. Conversely, minimal or no change in the expression of the above antigens occurs on monocyte-derived dendritic cells, because these molecules are already maximally expressed. However, both kinds of dendritic cells release interleukin-1β (IL-1β) and IL-12 after CD2 engagement. Lastly, interference with dendritic cell CD2–T-cell CD58 engagement decreases naive CD4+CD45RA+ T-cell proliferation. Collectively, our results suggest another role of the CD2-CD58 pathway that allows nonimmune and immune cells to interact directly with dendritic cells and initiate innate and adaptive immune responses.

scholarly journals Essential role of the adaptor protein Nck1 in Jurkat T cell activation and function

2011 ◽  
Vol 167 (1) ◽  
pp. 99-107 ◽  
Author(s):  
I. Yiemwattana ◽  
J. Ngoenkam ◽  
P. Paensuwan ◽  
R. Kriangkrai ◽  
B. Chuenjitkuntaworn ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Essential Role ◽  
Cell Activation ◽  
Adaptor Protein ◽  
Jurkat T Cell ◽  
And Function

scholarly journals Disc Large Homolog 1 is critical for early microcluster formation and activation in human T cells

2021 ◽  
Author(s):  
June Guha ◽  
Raj Chari
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Molecular Chaperone ◽  
Cell Activation ◽  
Synapse Formation ◽  
Immunological Synapse ◽  
Adaptor Protein ◽  
Tcr Signaling ◽  
Human T Cells

T cell activation by antigen involves multiple sequential steps, including TCR-microcluster (MC) formation, immunological synapse formation and phosphorylation of mediators downstream of the TCR. The adaptor protein Disc Large Homolog 1 (DLG1) is known to regulate proximal TCR signaling and, in turn, T cell activation, acting as a molecular chaperone that organizes specific kinases downstream of antigen recognition. Here, we report using knockdown and knockout studies in human T cells that DLG1 functions even earlier to regulate T cell activation by promoting TCR-MC formation. Moreover, we found that DLG1 can act as a bridge between the TCR-ζ chain and ZAP70 while inhibiting binding of the phosphatase SHP1 to TCR-ζ. Together, these effects drive dysregulation of T cell activation in DLG1-deficient T cells.

scholarly journals Uncovering a novel role of PLCβ4 in selectively mediating TCR signaling in CD8+ but not CD4+ T cells

2021 ◽  
Vol 218 (7) ◽  
Author(s):  
Miwa Sasai ◽  
Ji Su Ma ◽  
Masaaki Okamoto ◽  
Kohei Nishino ◽  
Hikaru Nagaoka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Tcr Signaling

Because of their common signaling molecules, the main T cell receptor (TCR) signaling cascades in CD4+ and CD8+ T cells are considered qualitatively identical. Herein, we show that TCR signaling in CD8+ T cells is qualitatively different from that in CD4+ T cells, since CD8α ignites another cardinal signaling cascade involving phospholipase C β4 (PLCβ4). TCR-mediated responses were severely impaired in PLCβ4-deficient CD8+ T cells, whereas those in CD4+ T cells were intact. PLCβ4-deficient CD8+ T cells showed perturbed activation of peripheral TCR signaling pathways downstream of IP3 generation. Binding of PLCβ4 to the cytoplasmic tail of CD8α was important for CD8+ T cell activation. Furthermore, GNAQ interacted with PLCβ4, mediated double phosphorylation on threonine 886 and serine 890 positions of PLCβ4, and activated CD8+ T cells in a PLCβ4-dependent fashion. PLCβ4-deficient mice exhibited defective antiparasitic host defense and antitumor immune responses. Altogether, PLCβ4 differentiates TCR signaling in CD4+ and CD8+ T cells and selectively promotes CD8+ T cell–dependent adaptive immunity.

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