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The role of SAP in antigen priming and differentiation of T lymphocytes

University of British Columbia

Mutations in the SH2D1A gene that encodes signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) cause X-linked lymphoproliferative disease (XLP), a congenital immunodeficiency defined by exquisite sensitivity to Epstein-Barr virus (EBV). Upon EBV infection, XLP patients develop fulminant infectious mononucleosis, characterized by massive expansions of EBV-infected B cells and susceptibility to malignant B cell lymphomas. The precise mechanism of how SAP mediates immunity against EBV remains unclear. Here, we utilized SAP-deficient (Sh2d1a-/-) mice to investigate the role of SAP in regulating T cell differentiation and function. We found that SAP-deficient CD4 and CD8 T cells had a diminished capacity to differentiate into IL-17-producing T helper (Th17) and T cytotoxic (Tc17) cells. The use of co-stimulating SLAM antibodies was found to augment the differentiation of IL-17-producing effectors in wild type but not Sh2d1a-/- splenic T cells under IL-17-polarizing conditions. Furthermore, Sh2d1a-/- mice were protected from experimental autoimmune encephalomyelitis (EAE) and exhibited decreased numbers of CNS-infiltrating Th17 and Tc17 effectors. Together, these results demonstrate that SAP signaling drives the differentiation and function of Th17 and Tc17 cells in vitro and in vivo. In addition, we hypothesized that SAP and SLAM family receptors may be critical for B cell-priming of antigen-specific CD8 T cells. To test this hypothesis, purified wild type and Sh2d1a-/- CD8 T cells were stimulated with various types of antigen-presenting cells (APCs) including B cells, B cell-depleted splenocytes and B lymphoma cells. We found that Sh2d1a-/- CD8 T cells exhibited diminished proliferation and effector functions when stimulated with antigen-presenting B cells or B lymphoma cells but not B cell-depleted splenocytes. In addition, wild type and Sh2d1a-/- CD8 T cells proliferated equivalently when cultured with non-SLAM family receptors-expression APCs: antigen-expressing melanoma or carcinoma cells. Together, these results identify a critical role for SAP and SLAM family receptors in the priming of CD8 T cells towards antigen-presenting B cells or B lymphoma cells. Collectively, our findings suggest that the susceptibility of XLP patients to EBV may be a consequence of virus’s B cell tropism and an inability of SAP-deficient naïve CD8 T cells to proliferate and differentiate upon encountering EBV-infected B cells.

Text

2016-12-31

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/55661

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/