scholarly journals The Same IκBα Mutation in Two Related Individuals Leads to Completely Different Clinical Syndromes

2004 ◽  
Vol 200 (5) ◽  
pp. 559-568 ◽  
Author(s):  
Riny Janssen ◽  
Annelies van Wengen ◽  
Marieke A. Hoeve ◽  
Monique ten Dam ◽  
Miriam van der Burg ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Nuclear Translocation ◽  
Ectodermal Dysplasia ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Immunoglobulin M ◽  
Heterozygous Mutation ◽  
Wild Type ◽  
Immunodeficiency Syndrome

Both innate and adaptive immune responses are dependent on activation of nuclear factor κB (NF-κB), induced upon binding of pathogen-associated molecular patterns to Toll-like receptors (TLRs). In murine models, defects in NF-κB pathway are often lethal and viable knockout mice have severe immune defects. Similarly, defects in the human NF-κB pathway described to date lead to severe clinical disease. Here, we describe a patient with a hyper immunoglobulin M–like immunodeficiency syndrome and ectodermal dysplasia. Monocytes did not produce interleukin 12p40 upon stimulation with various TLR stimuli and nuclear translocation of NF-κB was impaired. T cell receptor–mediated proliferation was also impaired. A heterozygous mutation was found at serine 32 in IκBα. Interestingly, his father has the same mutation but displays complex mosaicism. He does not display features of ectodermal dysplasia and did not suffer from serious infections with the exception of a relapsing Salmonella typhimurium infection. His monocyte function was impaired, whereas T cell function was relatively normal. Consistent with this, his T cells almost exclusively displayed the wild-type allele, whereas both alleles were present in his monocytes. We propose that the T and B cell compartment of the mosaic father arose as a result of selection of wild-type cells and that this underlies the widely different clinical phenotype.

scholarly journals GLK-IKKβ signaling induces dimerization and translocation of the AhR-RORγt complex in IL-17A induction and autoimmune disease

2018 ◽  
Vol 4 (9) ◽  
pp. eaat5401 ◽  
Author(s):  
Huai-Chia Chuang ◽  
Ching-Yi Tsai ◽  
Chia-Hsin Hsueh ◽  
Tse-Hua Tan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Nuclear Translocation ◽  
Retinoic Acid Receptor ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Orphan Nuclear Receptor ◽  
Tcr Signaling ◽  
Aryl Hydrocarbon

Retinoic-acid-receptor-related orphan nuclear receptor γt (RORγt) controls the transcription of interleukin-17A (IL-17A), which plays critical roles in the pathogenesis of autoimmune diseases. Severity of several human autoimmune diseases is correlated with frequencies of germinal center kinase–like kinase (GLK) (also known as MAP4K3)–overexpressing T cells; however, the mechanism of GLK overexpression–induced autoimmunity remains unclear. We report the signal transduction converging on aryl hydrocarbon receptor (AhR)–RORγt interaction to activate transcription of the IL-17A gene in T cells. T cell–specific GLK transgenic mice spontaneously developed autoimmune diseases with selective induction of IL-17A in T cells. In GLK transgenic T cells, protein kinase Cθ (PKCθ) phosphorylated AhR at Ser36 and induced AhR nuclear translocation. AhR also interacted with RORγt and transported RORγt into the nucleus. IKKβ (inhibitor of nuclear factor κB kinase β)–mediated RORγt Ser489 phosphorylation induced the AhR-RORγt interaction. T cell receptor (TCR) signaling also induced the novel RORγt phosphorylation and subsequent AhR-RORγt interaction. Collectively, TCR signaling or GLK overexpression induces IL-17A transcription through the IKKβ-mediated RORγt phosphorylation and the AhR-RORγt interaction in T cells. Our findings suggest that inhibitors of GLK or the AhR-RORγt complex could be used as IL-17A–blocking agents for IL-17A–mediated autoimmune diseases.

scholarly journals Genetic disruption of p38α Tyr323 phosphorylation prevents T-cell receptor–mediated p38α activation and impairs interferon-γ production

Blood ◽  
2009 ◽  
Vol 113 (10) ◽  
pp. 2229-2237 ◽  
Author(s):  
Ludmila Jirmanova ◽  
Dandapantula N. Sarma ◽  
Dragana Jankovic ◽  
Paul R. Mittelstadt ◽  
Jonathan D. Ashwell
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Function ◽  
Alternative Pathway ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Wild Type ◽  
T Helper 1 ◽  
Ifn Γ

AbstractT cells possess a p38 activation alternative pathway in which stimulation via the antigen receptor (T-cell receptor [TCR]) induces phosphorylation of p38α and β on Tyr323. To assess the contribution of this pathway to normal T-cell function, we generated p38α knockin mice in which Tyr323 was replaced with Phe (p38αY323F). TCR-mediated stimulation failed to activate p38αY323F as measured by phosphorylation of the Thr-Glu-Tyr activation motif and p38α catalytic activity. Cell-cycle entry was delayed in TCR-stimulated p38αY323F T cells, which also produced less interferon (IFN)–γ than wild-type T cells in response to TCR-mediated but not TCR-independent stimuli. p38αY323F mice immunized with T-helper 1 (Th1)–inducing antigens generated normal Th1 effector cells, but these cells produced less IFN-γ than wild-type cells when stimulated through the TCR. Thus, the Tyr323-dependent pathway and not the classic mitogen-activated protein (MAP) kinase cascade is the physiologic means of p38α activation through the TCR and is necessary for normal Th1 function but not Th1 generation.

Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor κB

Blood ◽  
2001 ◽  
Vol 98 (3) ◽  
pp. 743-753 ◽  
Author(s):  
Emira Ayroldi ◽  
Graziella Migliorati ◽  
Stefano Bruscoli ◽  
Cristina Marchetti ◽  
Ornella Zollo ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Leucine Zipper ◽  
Nuclear Translocation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Receptor Expression ◽  
Nuclear Factor

Abstract Previously a novel gene was identified that encodes a glucocorticoid-induced leucine zipper (GILZ) whose expression is up-regulated by dexamethasone. This study analyzed the role of GILZ in the control of T-cell activation and its possible interaction with nuclear factor κB (NF-κB). Results indicate that GILZ inhibits both T-cell receptor (TCR)–induced interleukin-2/interleukin-2 receptor expression and NF-κB activity. In particular, GILZ inhibits NF-κB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-κB subunits. Moreover, GILZ-mediated modulation of TCR-induced responses is part of a circuit because TCR triggering down-regulates GILZ expression. These results identify a new molecular mechanism involved in the dexamethasone-induced regulation of NF-κB activity and T-cell activation.

scholarly journals Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function

2012 ◽  
Vol 109 (5) ◽  
pp. 1625-1630 ◽  
Author(s):  
A. Zanin-Zhorov ◽  
J. Lin ◽  
J. Scher ◽  
S. Kumari ◽  
D. Blair ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Regulatory T Cell ◽  
Cell Function ◽  
Cell Receptor ◽  
Scaffold Protein ◽  
T Cell Function

scholarly journals Herpes Simplex Virus Remodels T-Cell Receptor Signaling, Resulting in p38-Dependent Selective Synthesis of Interleukin-10

2007 ◽  
Vol 81 (22) ◽  
pp. 12504-12514 ◽  
Author(s):  
Derek D. Sloan ◽  
Keith R. Jerome
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
T Cell Receptor ◽  
Intracellular Signaling ◽  
Cell Function ◽  
Cell Receptor ◽  
Interleukin 10 ◽  
Simplex Virus

ABSTRACT Herpes simplex virus (HSV)-specific T cells are essential for viral clearance. However, T cells do not prevent HSV latent infection or reactivation, suggesting that HSV has the potential to modulate T-cell function. T-cell receptor (TCR) stimulation is a potent and specific means of activating T cells. To investigate how HSV affects T-cell function, we have analyzed how HSV affects TCR-stimulated intracellular signaling and cytokine synthesis in mock-infected and HSV-infected T cells. Mock-infected T cells stimulated through the TCR synthesized a broad range of cytokines that included the proinflammatory cytokines tumor necrosis factor alpha, gamma interferon, and interleukin-2. In contrast, HSV-infected T cells stimulated through the TCR selectively synthesized interleukin-10, a cytokine that suppresses cellular immunity and favors viral replication. To achieve selective interleukin-10 synthesis, HSV differentially affected TCR signaling pathways. HSV inhibited TCR-stimulated formation of the linker for activation of the T-cell signaling complex, and HSV inhibited TCR-stimulated NF-κB activation. At the same time, HSV activated the p38 and JNK mitogen-activated protein kinases as well as the downstream transcription factors ATF-2 and c-Jun. HSV did not inhibit TCR-stimulated activation of STAT3, a transcription factor involved in interleukin-10 synthesis. The activation of p38 was required for interleukin-10 synthesis in HSV-infected T cells. The ability of HSV to differentially target intracellular signaling pathways and transform an activating stimulus into an immunosuppressive response represents a novel strategy for pathogen-mediated immune modulation. Selective, TCR-stimulated interleukin-10 synthesis may play an important role in HSV pathogenesis.

scholarly journals T Cell Receptor-induced Nuclear Factor κB (NF-κB) Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-mediated Calcium Entry

2016 ◽  
Vol 291 (16) ◽  
pp. 8440-8452 ◽  
Author(s):  
Xiaohong Liu ◽  
Corbett T. Berry ◽  
Gordon Ruthel ◽  
Jonathan J. Madara ◽  
Katelyn MacGillivray ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Transcriptional Activation ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Calcium Entry ◽  
Nuclear Factor

scholarly journals CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation

2014 ◽  
Vol 211 (13) ◽  
pp. 2519-2535 ◽  
Author(s):  
James M. Kennedy ◽  
Nassima Fodil ◽  
Sabrina Torre ◽  
Silayuv E. Bongfen ◽  
Jean-Frédéric Olivier ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Coiled Coil ◽  
Cell Receptor ◽  
Pleiotropic Effect ◽  
Experimental Cerebral Malaria ◽  
A Genome ◽  
Important Regulator

We used a genome-wide screen in mutagenized mice to identify genes which inactivation protects against lethal neuroinflammation during experimental cerebral malaria (ECM). We identified an ECM-protective mutation in coiled-coil domain containing protein 88b (Ccdc88b), a poorly annotated gene that is found expressed specifically in spleen, bone marrow, lymph nodes, and thymus. The CCDC88B protein is abundantly expressed in immune cells, including both CD4+ and CD8+ T lymphocytes, and in myeloid cells, and loss of CCDC88B protein expression has pleiotropic effects on T lymphocyte functions, including impaired maturation in vivo, significantly reduced activation, reduced cell division as well as impaired cytokine production (IFN-γ and TNF) in response to T cell receptor engagement, or to nonspecific stimuli in vitro, and during the course of P. berghei infection in vivo. This identifies CCDC88B as a novel and important regulator of T cell function. The human CCDC88B gene maps to the 11q13 locus that is associated with susceptibility to several inflammatory and auto-immune disorders. Our findings strongly suggest that CCDC88B is the morbid gene underlying the pleiotropic effect of the 11q13 locus on inflammation.

Effect of CD28 signal transduction on c-Rel in human peripheral blood T cells

1994 ◽  
Vol 14 (12) ◽  
pp. 7933-7942
Author(s):  
R G Bryan ◽  
Y Li ◽  
J H Lai ◽  
M Van ◽  
N R Rice ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Nuclear Translocation ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Cd28 Costimulation

Optimal T-cell activation requires both an antigen-specific signal delivered through the T-cell receptor and a costimulatory signal which can be delivered through the CD28 molecule. CD28 costimulation induces the expression of multiple lymphokines, including interleukin 2 (IL-2). Because the c-Rel transcription factor bound to and activated the CD28 response element within the IL-2 promoter, we focused our study on the mechanism of CD28-mediated regulation of c-Rel in human peripheral blood T cells. We showed that CD28 costimulation accelerated the kinetics of nuclear translocation of c-Rel (and its phosphorylated form), p50 (NFKB1), and p65 (RelA). The enhanced nuclear translocation of c-Rel correlated with the stimulation of Il-2 production and T-cell proliferation by several distinct anti-CD28 monoclonal antibodies. This is explained at least in part by the long-term downregulation of I kappa B alpha following CD28 signalling as opposed to phorbol myristate acetate alone. Furthermore, we showed that the c-Rel-containing CD28-responsive complex is enhanced by, but not specific to, CD28 costimulation. Our results indicate that c-Rel is one of the transcription factors targeted by CD28 signalling.

scholarly journals T Cell Receptor Specificity Is Critical for the Development of Epidermal γδ T Cells

2001 ◽  
Vol 194 (10) ◽  
pp. 1473-1483 ◽  
Author(s):  
Isabel Ferrero ◽  
Anne Wilson ◽  
Friedrich Beermann ◽  
Werner Held ◽  
H. Robson MacDonald
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Biology ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Wild Type ◽  
Normal Numbers ◽  
T Cell Biology

A particular feature of γδ T cell biology is that cells expressing T cell receptor (TCR) using specific Vγ/Vδ segments are localized in distinct epithelial sites, e.g., in mouse epidermis nearly all γδ T cells express Vγ3/Vδ1. These cells, referred to as dendritic epidermal T cells (DETC) originate from fetal Vγ3+ thymocytes. The role of γδ TCR specificity in DETC's migration/localization to the skin has remained controversial. To address this issue we have generated transgenic (Tg) mice expressing a TCR δ chain (Vδ6.3-Dδ1-Dδ2-Jδ1-Cδ), which can pair with Vγ3 in fetal thymocytes but is not normally expressed by DETC. In wild-type (wt) Vδ6.3Tg mice DETC were present and virtually all of them express Vδ6.3. However, DETC were absent in TCR-δ−/− Vδ6.3Tg mice, despite the fact that Vδ6.3Tg γδ T cells were present in normal numbers in other lymphoid and nonlymphoid tissues. In wt Vδ6.3Tg mice, a high proportion of in-frame Vδ1 transcripts were found in DETC, suggesting that the expression of an endogenous TCR-δ (most probably Vδ1) was required for the development of Vδ6.3+ epidermal γδ T cells. Collectively our data demonstrate that TCR specificity is essential for the development of γδ T cells in the epidermis. Moreover, they show that the TCR-δ locus is not allelically excluded.

scholarly journals T-cell Large Granular Lymphocytic Leukemia Manifesting in Patients with HIV-1 Infection: Cases Series and Review of the Literature

2018 ◽  
Vol 10 (1) ◽  
pp. e2018036
Author(s):  
Ashley M Rose ◽  
Leidy Isenalumhe ◽  
Magali VanDenBergh ◽  
Lubomir Sokol
Keyword(s):  
T Cell ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Large Granular Lymphocytic Leukemia ◽  
Initiation Of Therapy ◽  
Criteria For Diagnosis ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

We report five patients with human immunodeficiency virus-1/acquired immunodeficiency syndrome (HIV-1/AIDS) who developed T-cell large granular lymphocytic leukemia (T-LGLL). None of the patients fulfilled criteria for diagnosis of diffuse infiltrative lymphocyte syndrome (DILS) or HIV-associated CD8+ lymphocytosis syndrome at the time of diagnosis of LGLL. The immunophenotype of malignant T-cells was identical in three patients with co-expression of CD3, CD8, CD57, and T-cell receptor (TCR) alpha/beta. Three out of five patients were also diagnosed with clonal disorders of B-cell origin including diffuse large B-cell lymphoma, Burkitt’s lymphoma, and monoclonal gammopathy of undetermined significance (MGUS).  Two patients developed cytopenias due to T-LGLL prompting initiation of therapy. Our study suggests that chronic viral infection with HIV can contribute to evolution of T-LGLL. Clinical and laboratory characteristics of T-LGLL associated with HIV-1/AIDS resemble those of immunocompetent  patients.

Sign in / Sign up

Export Citation Format

Share Document