BTLA and HVEM Cross Talk Regulates Inhibition and Costimulation

Gavrieli, Maya; Šedý, John; Nelson, Christopher A.; Murphy, Kenneth M.

doi:10.1016/s0065-2776(06)92004-5

Cited by 37 publications

(34 citation statements)

References 104 publications

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“…4A). These results are in agreement with the inhibitory role that BTLA plays in T lymphocytes, which has been described extensively in the literature (24,25). The addition of BTLA-Fc to the cultures of CD4 and CD8 T cells substantially enhanced the percentage of Btla Ϫ/Ϫ cells undergoing proliferation (from 63% to 74% and from 45% to 72%, respectively).…”

Section: Btla Mediates Survival Of Activated T Cellssupporting

confidence: 91%

Unconventional ligand activation of herpesvirus entry mediator signals cell survival

Cheung¹,

Steinberg

Oborne³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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172

221

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The herpesvirus entry mediator (HVEM; TNFRSF14) activates NF-κB through the canonical TNF-related cytokine LIGHT, serving as a costimulatory pathway during activation of T cells. HVEM also functions as a ligand for the Ig superfamily members B and T lymphocyte attenuator (BTLA) and CD160, both of which limit inflammatory responses initiated by T cells. Emerging evidence indicates BTLA also promotes T cell survival, but its structural differences from LIGHT intimate BTLA is unlikely to function as an activator of HVEM. We demonstrate here that BTLA, CD160, and herpes simplex virus envelope glycoprotein D (gD) function as activating ligands for HVEM, promoting NF-κB activation and cell survival. Membrane-expressed BTLA and CD160, as well as soluble dimeric receptor surrogates BTLA-Fc and gD-Fc specifically activated HVEM-dependent NF-κB. BTLA and CD160 engagement induced recruitment of TNF receptor-associated factor 2 (TRAF2), but not TRAF3, to HVEM that specifically activated the RelA but not the RelB form of NF-κB in a mucosal epithelial tumor cell line. Moreover, Btla −/− T cells survived poorly following activation but were rescued with BTLA-Fc, indicating HVEM-BTLA bidirectional signaling may serve as a critical cell-survival system for lymphoid and epithelial cells.

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Section: Btla Mediates Survival Of Activated T Cellssupporting

confidence: 91%

Unconventional ligand activation of herpesvirus entry mediator signals cell survival

Cheung¹,

Steinberg

Oborne³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

172

221

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“…This non-canonical engagement of HVEM-BTLA induces an inhibitory signaling cascade regulating T and B cell proliferation. Following HVEM engagement, BTLA attenuates antigen-mediated signals through an ITIM/ ITSM-dependent recruitment of Src homology tyrosine phosphatase-1 and -2 [27]. Biochemical analyses demonstrated that LIGHT and BTLA engage HVEM at distinct sites, suggesting that HVEM constitutes a molecular switch between positive and inhibitory signaling [28][29][30].…”

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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“…Herpes virus entry mediator (HVEM), also designated TNFRSF14, binds the TNF superfamily homologue LIGHT (TNFSF14), the CD28 family homologue B and T lymphocyte attenuator (BTLA) (17), and CD160. HVEM is expressed by most cells of the immune system (T cells, B cells, NK cells, dendritic cells (DC), and monocytes) and by some nonimmune cells such as hepatocytes, intestinal epithelial cells, and smooth muscle cells.…”

mentioning

confidence: 99%

IL-22-Dependent Attenuation of T Cell-Dependent (ConA) Hepatitis in Herpes Virus Entry Mediator Deficiency

Wahl¹,

Wegenka²,

Leithäuser

et al. 2009

The Journal of Immunology

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Coinhibitors and costimulators control intrahepatic T cell responses that trigger acute hepatitis. We used the ConA-induced hepatitis model in the mouse to test if the coinhibitor herpes virus entry mediator (HVEM) modulates hepatitis-inducing T cell responses. Compared with ConA-injected, wild-type (wt) C57BL/6 (B6) mice, HVEM-deficient (HVEM−/−) B6 mice showed lower serum transaminase levels and lower proinflammatory IFN-γ, but higher protective IL-22 serum levels and an attenuated liver histopathology. The liver type I invariant NKT cell population that initiates acute hepatitis in this model was reduced in HVEM−/− mice but their surface phenotype was similar to that of untreated or ConA-treated wt controls. In response to mitogen injection, liver invariant NKT cells from HVEM−/− B6 mice produced in vivo more IL-22 but lower amounts of IFN-γ and IL-4 than wt controls. Bone marrow chimeras showed that HVEM deficiency of the liver nonparenchymal cell population, but not of the parenchymal cell population, mediated the attenuated course of the dendritic cell- and T cell-dependent ConA hepatitis. IL-22 is produced more efficiently by liver NKT cells from HVEM−/− than from wt mice, and its Ab-mediated neutralization of IL-22 aggravated the course of hepatitis in wt and HVEM−/− mice. Hence, HVEM expression promotes pathogenic, proinflammatory Th1 responses but down-modulates protective IL-22 responses of T cells in this model of acute hepatitis.

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BTLA and HVEM Cross Talk Regulates Inhibition and Costimulation

Cited by 37 publications

References 104 publications

Unconventional ligand activation of herpesvirus entry mediator signals cell survival

Unconventional ligand activation of herpesvirus entry mediator signals cell survival

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

IL-22-Dependent Attenuation of T Cell-Dependent (ConA) Hepatitis in Herpes Virus Entry Mediator Deficiency

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