CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator

Cai, Guifang; Anumanthan, Anukanth; Brown, Julia A.; Greenfield, Edward; Zhu, Baogong; Freeman, Gordon J.

doi:10.1038/ni1554

Cited by 309 publications

(443 citation statements)

References 36 publications

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“…Our data suggest that this increased potency would result at least in part from impairment of host Treg responses. Second, in addition to the inhibitory HVEM/BTLA interaction, HVEM was shown to bind to CD160 on T cells and inhibit T cell activation (34). In this case, our data would suggest that HVEM expression by Tregs can exert inhibitory effects via ligation of BTLA or CD160 on Teff cells.…”

Section: Discussionmentioning

confidence: 83%

Regulatory T Cell Expression of Herpesvirus Entry Mediator Suppresses the Function of B and T Lymphocyte Attenuator-Positive Effector T Cells

Tao

Wang

Murphy

et al. 2008

The Journal of Immunology

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The binding of herpesvirus entry mediator (HVEM) to B and T lymphocyte attenuator (BTLA) is known to activate an inhibitory signaling cascade in effector T (Teff) cells, but we now report that the HVEM-BTLA pathway is also important to the suppressive function of regulatory T cells (Tregs). Although naive T cells up-regulated BTLA upon TCR activation, Treg expression of BTLA remained low, regardless of TCR activation. Moreover, BTLA−/− CD4+CD25+ Tregs had normal suppressive activity, whereas BTLA−/− Teff cells were more resistant than wild-type Teff cells to suppression by Tregs, suggesting BTLA expression by Teff cells was required for their suppression by Tregs. In contrast to BTLA, HVEM expression was comparable in naive Tregs vs Teff cells, but after stimulation HVEM expression was quickly down-regulated by Teff cells, whereas HVEM was further up-regulated by Tregs. HVEM−/− Tregs had decreased suppressive activity as compared with wild-type Tregs, indicating that Treg expression of HVEM was required for optimal suppression. Consistent with this, T cells from Scurfy mice (FoxP3 mutant) lacked HVEM gene expression, and adoptively transferred wild-type but not HVEM−/− Tregs were able to control alloresponses in vivo by normal Teff cells. Our data demonstrate that Tregs can exert their effects via up-regulation of the negative costimulatory ligand HVEM, which upon binding to BTLA expressed by Teff cells helps mediate the suppressive functions of Tregs in vitro and in vivo.

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Section: Discussionmentioning

confidence: 83%

Regulatory T Cell Expression of Herpesvirus Entry Mediator Suppresses the Function of B and T Lymphocyte Attenuator-Positive Effector T Cells

Tao

Wang

Murphy

et al. 2008

The Journal of Immunology

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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%

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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“…However, it is unlikely that this interaction plays a role in B cell physiology, as CD160 is not expressed on B cells. Furthermore, the only HVEM binding partner that is present on mature, naive B cells appears to be BTLA (17)(18)(19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK

Vendel¹,

Calemine-Fenaux²,

Izrael-Tomasevic³

et al. 2009

The Journal of Immunology

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B and T lymphocyte attenuator (BTLA) functions as a negative regulator of T cell activation and proliferation. Although the role of BTLA in regulating T cell responses has been characterized, a thorough investigation into the precise molecular mechanisms involved in BTLA-mediated lymphocyte attenuation and, more specifically, its role in regulating B cell activation has not been presented. In this study, we have begun to elucidate the biochemical mechanisms by which BTLA functions to inhibit B cell activation. We describe the cell surface expression of BTLA on various human B cell subsets and confirm its ability to attenuate B cell proliferation upon associating with its known ligand, herpesvirus entry mediator (HVEM). BTLA associates with the BCR and, upon binding to HVEM, recruits the tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 and reduces activation of signaling molecules downstream of the BCR. This is exemplified by a quantifiable decrease in tyrosine phosphorylation of the protein tyrosine kinase Syk, as measured by absolute quantification mass spectrometry. T he B and T lymphocyte attenuator (BTLA) 2 is an Ig superfamily coinhibitory receptor with structural and functional similarities to programmed cell death 1 (PD-1) and CTLA-4 (1-3). However, unlike PD-1 and CTLA-4, which bind members of the B7 Ig superfamily receptors, the established ligand for BTLA is the TNFR family member herpesvirus entry mediator (HVEM) (TNFRSF14) (3-5). HVEM binding leads to tyrosine phosphorylation of the cytoplasmic tail of BTLA, which contains a proposed Grb2/Grb2-related adaptor protein (Grap) docking site and two ITIMs (5-11). Biochemical analysis has revealed that phosphorylation at multiple tyrosines within the cytoplasmic tail of BTLA is necessary and required for efficient recruitment of protein tyrosine phosphatases and BTLA-mediated attenuation of T cell effector response and cell proliferation (5,8,10,11).The role of BTLA appears to be limited to lymphocyte activation as shown in BTLA-deficient mice, which present normal lymphoid organ development and near wild-type lymphocyte numbers. However, these mice display hyperproliferative T and B cell responses to TCR-and BCR-mediated activation, respectively (9, 11). Furthermore, loss of BTLA function leads to increased susceptibility to experimental autoimmune encephalomyelitis and MHC-mismatched allograft rejection, supporting the role of BTLA in modulating T cell activation and effector responses (11,12).Surface expression analysis of BTLA indicates that it is expressed on a wide number of lymphocytes in mice. It is most highly expressed on B cells, followed by CD4 ϩ T cells, and lower expression on CD8 ϩ T cells, macrophages, dendritic cells, and NK cells (9, 13). During murine B cell development, BTLA expression first appears in pre-B cells and shows increased expression through B cell maturation, with the highest expression on mature B cells (9). In this study, we show a detailed cell surface expression profile of BTLA during human B cell deve...

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CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator

Cited by 309 publications

References 36 publications

Regulatory T Cell Expression of Herpesvirus Entry Mediator Suppresses the Function of B and T Lymphocyte Attenuator-Positive Effector T Cells

Regulatory T Cell Expression of Herpesvirus Entry Mediator Suppresses the Function of B and T Lymphocyte Attenuator-Positive Effector T Cells

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

B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK

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