2B4-SAP signaling is required for the priming of naive CD8⁺ T cells by antigen-expressing B cells and B lymphoma cells

Abstract

Mutations in SH2D1A gene 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 CD8C 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 C 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 C T cells responded equivalently to wild-type CD8 C 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 C 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 C T cell proliferation and differentiation. Altogether, a pivotal role for SAP in promoting the expansion and differentiation of B cell-primed viral-specific naive CD8C T cells may explain the selective immune deficiency of XLP patients to EBV and B cell lymphomas.

Adaptor proteins: Flexible and dynamic modulators of immune cell signalling

“…In the absence of SAP, signalling through the SLAM receptor 2B4 is disrupted in T cells and proper activation of naïve CD8 + T cells is abolished. 147 Together, this illustrates how SAP may be involved in signal attenuation as well as signal multiplication, as discussed earlier (Figure 2C and 2F).…”

Serious consequences of Epstein‐Barr virus infection: Hemophagocytic lymphohistocytosis

“…The antigen persists, which results in proliferation of human lymphocytes and tissue cells, secreting a large number of cytokines, causing a cytokine storm, leading to disease 5,6 . On the other hand, EBV infects T lymphocytes and can express latent membrane protein 1 (LMP‐1), 7 which causes cytokine storms through tumor necrosis factor‐related factors and nuclear factor pathways, which do harm to the body's extensive tissue organs. LMP‐1 can also be applied to increase the level of activated transcription factor 5, thereby inhibiting the expression of the signaling lymphocyte activation molecule (SLAM) associated protein (SAP), SAP dysfunction, loss of its regulatory function, and overactivation of T lymphocytes, resulting in cytokine storms 7 .…”

“…LMP‐1 can also be applied to increase the level of activated transcription factor 5, thereby inhibiting the expression of the signaling lymphocyte activation molecule (SLAM) associated protein (SAP), SAP dysfunction, loss of its regulatory function, and overactivation of T lymphocytes, resulting in cytokine storms 7 . So, LMP‐1 and SAP are probably the most critical factors in EBV‐HLH pathogenesis 7 …”

TLR1/2 Specific Small‐Molecule Agonist Suppresses Leukemia Cancer Cell Growth by Stimulating Cytotoxic T Lymphocytes

“…With the excellent simulation of immune responses in cells and having target specificity in biophysical experiments, we explored the anti‐tumor immunity of SMU‐Z1 both in vitro and in vivo. Mouse primary splenocytes are mainly composed of B and T cells, and may contain about 10% antigen‐presenting cells (APCs) as well as other cells . In this study, the effects of SMU‐Z1 on splenocyte proliferation and their viability were measured by CCK8 after treatment with SMU‐Z1 for 48 h ( Figure A) in male C57Bl/6 (C57) mice.…”