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

Abstract

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...

BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

“…C TIL after TCR activation and could potentially interact with HVEM, a prosurvival effect mediated through LIGHT is unlikely because it has no obvious signaling motif, 44 and it has been reported that signaling through HVEM upon binding to LIGHT might induce a different T-cell survival via NF-kB activation. 45 It is also possible that cis interaction or a T-T interaction between BTLA and HVEM could mediate survival via HVEM, as shown by Carl Ware's group.…”

Expression of a Broad Array of Negative Costimulatory Molecules and Blimp-1 in T Cells following Priming by HIV-1 Pulsed Dendritic Cells

“…Hence, TRAIL could be another potential negative factor contributing to T-cell suppression in HIV infection. BTLA (CD272) inhibits TCR-mediated signaling via its immunoreceptor tyrosine-based inhibitory and switch motifs (18,62). Likewise, CD160 mediates negative signaling and is induced in a similar manner as CTLA-4 in T cells (16).…”

TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses

“…However, as previous studies suggest that TNFRSF14 aberrations may confer a poor prognosis in patients treated with chemoimmunotherapy, 4 it is likely that additional or alternative HVEM-mediated mechanisms impact on FL B-cell survival in the autologous setting. As BTLA is also expressed on B cells, and negatively regulates B-lymphocyte transformation and malignant B-cell survival, [35][36][37] reduction of HVEM ligation of BTLA on FL B cells either in cis or trans (from neighboring tumor cells) could potentiate tumor growth and survival in this setting.…”