B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator

Šedý, John; Gavrieli, Maya; Potter, Karen G.; Hurchla, Michelle A.; Lindsley, R. Coleman; Hildner, Kai; Scheu, Stefanie; Pfeffer, Klaus; Ware, Carl F.; Murphy, Theresa L.; Murphy, Kenneth M.

doi:10.1038/ni1144

Cited by 552 publications

(580 citation statements)

References 34 publications

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“…Thus, HVEM-Ig might inhibit T cell proliferation through an indirect effect against APCs in addition to the direct effect against T cells. On the other hand, HVEM is also known to bind to BTLA and CD160 expressed on T cells (del Rio et al 2010) and to induce coinhibitory signal (Cai et al 2008;Sedy et al 2005), raising the possibility that HVEM-Ig might stimulate this coinhibitory signaling. However, BTLA was reported to induce cell death in T cells in some cases (Deppong et al 2008), but we did not detect any additional T cell death by HVEM-Ig treatment (Fig.4).…”

Section: Discussionmentioning

confidence: 99%

“…HVEM, initially identified as a herpes virus receptor, regulates T cell proliferation positively or negatively depending on its ligands (Cai and Freeman 2009). HVEM binds to LIGHT, augmenting T cell proliferation and IFN-γ production (Harrop et al 1998;Tamada et al 2000), whereas its binding to BTLA and CD160 negatively regulates T cell proliferation (Cai et al 2008;Sedy et al 2005). ICOS also enhances T cell activation, although it seems to be more important for differentiation of activated T cells (McAdam et al 2000).…”

Section: Introductionmentioning

confidence: 99%

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Concanavalin A-mediated T cell proliferation is regulated by herpes virus entry mediator costimulatory molecule

Ando

Yasuoka

Mishima

et al. 2013

In Vitro Cell.Dev.Biol.-Animal

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T cell activation is regulated by two distinct signals, signal one and two. Concanavalin A (ConA) is an antigen-independent mitogen and functions as signal one inducer, leading T cells to polyclonal proliferation. CD28 is known to be one of major costimulatory receptors and to provide signal two in the ConA-induced T cell proliferation. Here, we have studied the implication of other costimulatory pathways in the ConA-mediated T cell proliferation by using soluble recombinant proteins consisting of an extracellular domain of costimulatory receptors and Fc portion of human IgG. We found that T cell proliferation induced by ConA, but not PMA plus ionomycin or anti-CD3 mAb, is significantly inhibited by HVEM-Ig, even in the presence of CD28 signaling. Moreover, the high concentration of HVEM-Ig molecules almost completely suppressed ConA-mediated T cell proliferation. These results suggest that HVEM might play more important roles than CD28 in ConA-mediated T cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Concanavalin A-mediated T cell proliferation is regulated by herpes virus entry mediator costimulatory molecule

Ando

Yasuoka

Mishima

et al. 2013

In Vitro Cell.Dev.Biol.-Animal

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“…Our studies failed to show any efficacy of LIGHT in human T cell activation, even though it was highly expressed on recombinant AdV modified-monocytes and capable of binding anti-LIGHT as well as its known receptors. Recent evidence shows that in addition to acting as a receptor for LIGHT, HVEM can function as a ligand for the immunoreceptor tyrosine inhibitory motif-containing receptor, B and T lymphocyte attenuator (55,56). Thus, it is possible that HVEM-B and T lymphocyte attenuator interaction predominates during T cell activation resulting in minimal impact of HVEM signaling in T cells.…”

Section: Discussionmentioning

confidence: 99%

4-1BBL Induces TNF Receptor-Associated Factor 1-Dependent Bim Modulation in Human T Cells and Is a Critical Component in the Costimulation-Dependent Rescue of Functionally Impaired HIV-Specific CD8 T Cells

Wang

Wen

Routy

et al. 2007

The Journal of Immunology

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During chronic infection, HIV-specific CD8 T cells exhibit progressive signs of functional impairment, attributed to persistent antigenic stimulation, up-regulation of the inhibitory receptor PD-1, and declining T cell help. Strategies that directly improve CD8 T cell function offer the potential of restoring immune control of HIV. Although PD-1 expression has been identified as a cause of functional impairment in HIV, in this study, PD-1 expression was observed on only a subfraction of HIV-specific CD8 T cells in a subfraction of donors, whereas HIV-specific CTL from all donors exhibited a limited repertoire of effector functions. CD137L (4-1BBL) is emerging as an important stimulator of antiviral CD8 T cell responses. Regardless of the PD-1 status of the donors, here we show that 4-1BBL, when combined with CD80 or CD70, expands a population of Ag-specific CD8 T cells expressing multiple markers of effector function, from the functionally impaired starting population. In contrast, CD70 in combination with CD80 was insufficient for these effects and the related TNF family ligand, LIGHT, had negligible activity. The unique contribution of 4-1BBL correlated with down-regulation of the proapoptotic molecule Bim in activated CD8 T cells. Decreasing the level of TNFR-associated factor 1 in T cells using small interfering RNA resulted in increased levels of Bim in the 4-1BBL-stimulated T cells. Thus, costimulation via 4-1BBL leads to TNFR-associated factor 1-dependent Bim down-modulation in T cells, resulting in increased T cell expansion. These studies identify 4-1BBL as a critical component in therapeutic strategies aimed at improving CD8 T cell function.

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“…HVEM interacts with an inhibitory receptor, B and T lymphocyte attenuator (BTLA), an immunoglobulin (Ig) superfamily (Figure 2) [25,26], known to attenuate lymphocyte activation, and thus a candidate regulator for DC. This non-canonical engagement of HVEM-BTLA induces an inhibitory signaling cascade regulating T and B cell proliferation.…”

Section: Counter Regulatory Mechanism For Dc: the Hvem-btla Pathwaymentioning

confidence: 99%

The TNF receptor and Ig superfamily members form an integrated signaling circuit controlling dendritic cell homeostasis

Trez

Ware

2008

Cytokine & Growth Factor Reviews

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Dendritic cells (DC) constitute the most potent antigen presenting cells of the immune system, playing a key role bridging innate and adaptive immune responses. Specialized DC subsets differ depending on their origin, tissue location and the influence of trophic factors, the latter remain to be fully understood. Stromal cell and myeloid-associated Lymphotoxin-β receptor (LTβR) signaling is required for the local proliferation of lymphoid tissue DC. This review focuses the LTβR signaling cascade as a crucial positive trophic signal in the homeostasis of DC subsets. The noncanonical coreceptor pathway comprised of the Immunoglobulin (Ig) superfamily member, B and T lymphocyte attenuator (BTLA) and TNFR superfamily member, Herpesvirus entry mediator (HVEM) counter regulates the trophic signaling by LTβR. Together both pathways form an integrated signaling circuit achieving homeostasis of DC subsets.Keywords dendritic cells; homeostasis; TNF superfamily; cosignaling; lymphotoxin; herpesvirus entry mediator Dendritic CellsDendritic cells (DC) originate from hematopoietic precursors and can be divided in several subsets depending on their anatomical location, surface phenotype and function. For example, two broad classes of DC are the peripheral migratory DC and the lymphoid tissue-resident DC [1]. The migratory DC, i.e. the dermal DC and Langerhans cells, can be considered as sentinels of the immune system as they form a sensing barrier in peripheral tissues at the interface with environment. The lymphoid tissue-resident DC include the splenic and thymic DC.Dendritic cells are specialized in the capture, transport, processing and presentation of antigens. In the presence of a microbial stimulus, these steps are associated with further DC differentiation (maturation) characterized by upregulation of costimulatory and major histocompatibility complex (MHC) molecules. As DC become activated they migrate to or Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Both spleen and lymph node lymphoid tissue-resident DC possess a half-life of about three days. Despite their rapid turnover, little is known about the factors controlling immediate precursors and homeostasis in vivo. In earlier studies, CD8α expression was used to distinguish between "lymphoid" and "myeloid" DC. However, more recent experiments showed that different DC subsets could differentiate from both lymphoid and myeloid precursors [6,7]. CD8α marker remains very useful to discriminate between subsets, but no longer defines a subset origin. Recently, the group of Shortman provided in vivo and in vitro evidence fo...

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B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator

Cited by 552 publications

References 34 publications

Concanavalin A-mediated T cell proliferation is regulated by herpes virus entry mediator costimulatory molecule

Concanavalin A-mediated T cell proliferation is regulated by herpes virus entry mediator costimulatory molecule

4-1BBL Induces TNF Receptor-Associated Factor 1-Dependent Bim Modulation in Human T Cells and Is a Critical Component in the Costimulation-Dependent Rescue of Functionally Impaired HIV-Specific CD8 T Cells

The TNF receptor and Ig superfamily members form an integrated signaling circuit controlling dendritic cell homeostasis

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