Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2

Gavrieli, Maya; Watanabe, Norihiko; Loftin, Susan K.; Murphy, Theresa L.; Murphy, Kenneth M.

doi:10.1016/j.bbrc.2003.11.070

Cited by 175 publications

(167 citation statements)

References 37 publications

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“…The ligand for BTLA is the TNF receptor HVEM, which is unique in that it is the first example of an Ig superfamily receptor interacting with a TNF family member (4,5). In T cells, activation of BTLA leads to tyrosine phosphorylation of ITIM domains located within its cytoplasmic tail, which leads to recruitment of the phosphatase SHP1 and inhibition of undefined positive signaling molecules (6,8,11). Although BTLA recruits SHP1, the precise mechanisms involved in BTLA-mediated lymphocyte attenuation are unclear (6,8).…”

Section: Discussionmentioning

confidence: 99%

“…In T cells, activation of BTLA leads to tyrosine phosphorylation of ITIM domains located within its cytoplasmic tail, which leads to recruitment of the phosphatase SHP1 and inhibition of undefined positive signaling molecules (6,8,11). Although BTLA recruits SHP1, the precise mechanisms involved in BTLA-mediated lymphocyte attenuation are unclear (6,8). Furthermore, little work has been done to elucidate the role of BTLA in other lymphocytes, including B cells.…”

Section: Discussionmentioning

confidence: 99%

“…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)(4)(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)(6)(7)(8)(9)(10)(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).…”

mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…BTLA intracellular domain has two immunoreceptor tyrosine-based inhibitory motifs (ITIM) that recruit phosphatases SHP1 and SHP2 [53], which mediate the inhibitory function of BTLA. The permanent expression of BTLA on Th1 cells and absence on Th2 cells when they undergo secondary activation strongly suggest that BTLA may regulate Th1 function.…”

Section: B-and T-lymphocyte Attenuator-mentioning

confidence: 99%

Inhibitory costimulation and anti-tumor immunity

Martín‐Orozco

Dong²

2007

Seminars in Cancer Biology

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Costimulation was originally shown to be important in T-cell activation and effector differentiation. Recent characterization of B7/butyrophilin and members of the CD28 superfamily has revealed a large number of negative costimulatory molecules that dampen T-cell activation and regulate immune tolerance. Some of these molecules have been shown to be upregulated in the tumor microenvironment and may serve as potential targets for augmenting anti-tumor immunity. In this article, we summarize recent developments in the field of inhibitory costimulation and discuss the future direction of therapeutic manipulation of inhibitory costimulation in tumor immunotherapy.

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“…Additionally, Cdk6-null mice do not have abnormal thymocyte development [318] suggesting that a reduction in cdk6 mRNA is not the cause of the severely reduced number of Myb-deficient thymocytes. Btla is an inhibitory surface receptor expressed in activated Th1 thymocytes which associates with protein phosphatases SHP1 and SHP2 [319]. Btla-null mice do not have a defect in T cell development [320] but that does not rule out the possibility that over-expression of Btla may negatively affect T cell development.…”

Section: Itga9mentioning

confidence: 99%

MYB IS Required for B-Selection During Thymopoises

Duley¹

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Abstractc-Myb is a transcription factor required during hematopoiesis and is crucial for multiple stages of thymopoiesis. Understanding c-Myb function during hematopoiesis has been greatly impeded due to the lack of a tractable genetic system. We have used the Cre/loxP approach to conditional mutagenesis to study c-Myb function during thymopoiesis. Thymocyte specific inactivation of the Myb locus demonstrated a block in DN3 to DN4 differentiation concomitant with impaired Vβ to DJβ recombination of the Tcrb locus suggesting that the inability to generate a TCRβ protein blocked DN3 differentiation. However, some DN3 thymocytes

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Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2

Cited by 175 publications

References 37 publications

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

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

Inhibitory costimulation and anti-tumor immunity

MYB IS Required for B-Selection During Thymopoises

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