Essential Role of E3 Ubiquitin Ligase Activity in <i>Cbl-b–</i>Regulated T Cell Functions

Paolino, Magdalena; Thien, Christine B.F.; Gruber, Thomas; Hinterleitner, Reinhard; Baier, Gottfried; Langdon, Wallace Y.; Penninger, Josef

doi:10.4049/jimmunol.1003390

Cited by 77 publications

(91 citation statements)

References 44 publications

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“…A larger number of samples would likely be needed to identify gene-expression patterns associated with clinical outcomes. Of note, several negative regulators of cell function were overexpressed in persisting lymphocytes, including FOXP1, 23 CBL-B, [24][25][26] 14 HVEM can be a ligand for inhibitory or stimulatory receptors expressed in T cells 15,16 and has been described as a mechanism of inhibition induced by regulatory T cells. 35 Its role as a ligand is particularly relevant in the immune response against melanoma tumors, which express HVEM at high frequency.…”

Section: Discussionmentioning

confidence: 99%

Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes

Abate-Daga

Hanada

Davis

et al. 2013

Blood

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Key Points• Gene expression in TCRengineered cells resembles that of virus-reactive cells more than native tumor antigen-reactive cells.• Persisting TCR gene-engineered T cells are sensitive to PD-L1-PD-1 interaction but CD160-associated impairment is ligand-independent.Despite significant progress in the development of adoptive cell-transfer therapies (ACTs) using gene-engineered T cells, little is known about the fate of cells following infusion. To address that, we performed a comparative analysis of gene expression between T-cell receptor-engineered lymphocytes persisting in the circulation 1 month after administration and the product that was infused. We observed that 156 genes related to immune function were differentially expressed, including underexpression of stimulators of lymphocyte function and overexpression of inhibitory genes in postinfusion cells. Of genes overexpressed postinfusion, the product of programmed cell death 1 (PDCD1), coinhibitory receptor PD-1, was expressed at a higher percentage in postinfusion lymphocytes than in the infusion product. This was associated with a higher sensitivity to inhibition of cytokine production by interaction with its ligand PD-L1. Coinhibitory receptor CD160 was also overexpressed in persisting cells, and its expression was associated with decreased reactivity, which surprisingly was found to be ligand-independent. These results contribute to a deeper understanding of the properties of transgenic lymphocytes used to treat human malignancies and may provide a rationale for the development of combination therapies as a method to improve ACT. This trial was registered at www.clinicaltrials.gov as #NCT00509288, #NCT00923195, and

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Section: Discussionmentioning

confidence: 99%

Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes

Abate-Daga

Hanada

Davis

et al. 2013

Blood

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“…Many of the molecular processes involved in maintenance of T cell anergy by these E3 ligases remain incompletely understood. For example, only recently was the indispensable role of RING finger E3 ligase activity of Cbl-b in in vivo tolerance confirmed (16).…”

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confidence: 99%

Deltex1 Promotes Protein Kinase Cθ Degradation and Sustains Casitas B-Lineage Lymphoma Expression

Hsu

Hsiao

et al. 2014

The Journal of Immunology

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The generation of T cell anergy is associated with upregulation of ubiquitin E3 ligases including Casitas B-lineage lymphoma (Cbl-b), Itch, gene related to anergy in lymphocyte, and deltex1 (DTX1). These E3 ligases attenuate T cell activation by targeting to signaling molecules. For example, Cbl-b and Itch promote the degradation of protein kinase Cθ (PKCθ) and phospholipase C-γ1 (PLC-γ1) in anergic Th1 cells. How these anergy-associated E3 ligases coordinate during T cell anergy remains largely unknown. In the current study, we found that PKCθ and PLC-γ1 are also downregulated by DTX1. DTX1 interacted with PKCθ and PLC-γ1 and stimulated the degradation of PKCθ and PLC-γ1. T cell anergy–induced proteolysis of PKCθ was prevented in Dtx1−/− T cells, supporting the essential role of DTX1 in PKCθ downregulation. Similar to Cbl-b and Itch, DTX1 promoted monoubiquitination of PKCθ. Proteasome inhibitor did not inhibit DTX1-directed PKCθ degradation, but instead DTX1 directed the relocalization of PKCθ into the lysosomal pathway. In addition, DTX1 interacted with Cbl-b and increased the protein levels of Cbl-b. We further demonstrated the possibility that, through the downregulation of PKCθ, DTX1 prevented PKCθ-induced Cbl-b degradation and increased Cbl-b protein stability. Our results suggest the coordination between E3 ligases during T cell anergy; DTX1 acts with Cbl-b to assure a more extensive silencing of PKCθ, whereas DTX1-mediated PKCθ degradation further stabilizes Cbl-b.

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“…Specifically, CBL-B provides a check for costimulation of the B cell receptor (BCR) or T cell receptor (TCR) (by CD40 or CD28, respectively; Chiang et al 2000;Loeser and Penninger 2007;Sohn et al 2003). Without secondary stimulation, CBL-B targets downstream signaling molecules for ubiquitination, which ultimately induces B and T cell anergy (Paolino et al 2011;Qiao et al 2007;Sohn et al 2003). In poultry, dietary aflatoxins diminish T lymphocyte activation (Giambrone et al 1985;Ghosh et al 1991) and reduce antibody titers (Thaxton et al 1974;Verma et al 2004).…”

Section: Afb 1 and Adaptive Immunitymentioning

confidence: 99%

Modulation of the spleen transcriptome in domestic turkey (Meleagris gallopavo) in response to aflatoxin B1 and probiotics

et al. 2015

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Poultry are highly susceptible to the immunotoxic effects of the food-borne mycotoxin aflatoxin B1 (AFB1). Exposure impairs cell-mediated and humoral immunity, limits vaccine efficacy, and increases the incidence of costly secondary infections. We investigated the molecular mechanisms of AFB1 immunotoxicity and the ability of a Lactobacillus-based probiotic to protect against aflatoxicosis in the domestic turkey (Meleagris gallopavo). The spleen transcriptome was examined by RNA sequencing (RNA-seq) of 12 individuals representing four treatment groups. Sequences (6.9 Gb) were de novo assembled to produce over 270,000 predicted transcripts and transcript fragments. Differential expression analysis identified 982 transcripts with statistical significance in at least one comparison between treatment groups. Transcripts with known immune functions comprised 27.6 % of significant expression changes in the AFB1-exposed group. Short exposure to AFB1 suppressed innate immune transcripts, especially from antimicrobial genes, but increased the expression of transcripts from E3 ubiquitin-protein ligase CBL-B and multiple interleukin-2 response genes. Up-regulation of transcripts from lymphotactin, granzyme A, and perforin 1 could indicate either increased cytotoxic potential or activation-induced cell death in the spleen during aflatoxicosis. Supplementation with probiotics was found to ameliorate AFB1-induced expression changes for multiple transcripts from antimicrobial and IL-2-response genes. However, probiotics had an overall suppressive effect on immune-related transcripts.

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Essential Role of E3 Ubiquitin Ligase Activity in Cbl-b–Regulated T Cell Functions

Cited by 77 publications

References 44 publications

Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes

Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes

Deltex1 Promotes Protein Kinase Cθ Degradation and Sustains Casitas B-Lineage Lymphoma Expression

Modulation of the spleen transcriptome in domestic turkey (Meleagris gallopavo) in response to aflatoxin B1 and probiotics

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