title: 2B4-SAP signaling is required for the priming of naive CD8+T cells by antigen-expressing B cells and B lymphoma cells.
abstract: Mutations inSH2D1Agene that encodes SAP (SLAM-associated protein) result in X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency disease defined by exquisite sensitivity to the B-lymphotropic Epstein-Barr virus (EBV) and B cell lymphomas. However, the precise mechanism of how the loss of SAP function contributes to extreme vulnerability to EBV and the development of B cell lymphomas remains unclear. Here, we investigate the hypothesis that SAP is critical for CD8+T cell immune surveillance of antigen (Ag)-expressing B cells or B lymphoma cells under conditions of defined T cell receptor (TCR) signaling.Sh2d1a-/-CD8+T cells exhibited greatly diminished proliferation relative to wild type when Ag-presenting-B cells or -B lymphoma cells served as the primary Ag-presenting cell (APC). By contrast,Sh2d1a-/-CD8+T cells responded equivalently to wild-type CD8+T cells when B cell-depleted splenocytes, melanoma cells or breast carcinoma cells performed Ag presentation. Through application of signaling lymphocyte activation molecule (SLAM) family receptor blocking antibodies or SLAM family receptor-deficient CD8+T cells and APCs, we found that CD48 engagement on the B cell surface by 2B4 is crucial for initiating SAP-dependent signaling required for the Ag-driven CD8+T cell proliferation and differentiation. Altogether, a pivotal role for SAP in promoting the expansion and differentiation of B cell-primed viral-specific naive CD8+T cells may explain the selective immune deficiency of XLP patients to EBV and B cell lymphomas.
authors.affiliation: British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Huang
authors.affiliation: British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Tsai
authors.affiliation: British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sara Y
authors.initials: SY
authors.lastname: Tan
authors.affiliation: British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sohyeong
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Surgery, Emory University , Atlanta, GA, USA.
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia , Vancouver, British Columbia, Canada.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Harder
authors.affiliation: British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: John J
authors.initials: JJ
authors.lastname: Priatel
keywords: Antigen-presenting cells; B cell lymphoma; B cells; CD8+ T cells; Epstein–Barr virus; SLAM family receptors; SLAM-associated protein; T cell receptor; X-linked proliferative disease; immune deficiency