SAP expression in T cells, not in B cells, is required for humoral immunity

Abstract

SAP (also named SH2D1A) is an intracellular adaptor molecule expressed in T cells, natural killer (NK) cells, and some B cells. The SAP gene is mutated in X-linked lymphoproliferative (XLP) disease, a human immunodeficiency characterized by a faulty immune response to Epstein-Barr virus infection. Previous reports documented severe defects in antibody production and germinal center (GC) formation in SAP-deficient humans and mice genetically engineered to lack SAP expression. However, in vitro studies and adoptive transfer experiments provided conflicting data as to whether this phenotype is caused by a functional defect resulting from SAP deficiency in T cells, B cells, or both. Here, we ascertained which cell types are responsible for this humoral immunity defect by using a conditional gene targeting approach. We also thoroughly examined the expression pattern of SAP in normal immune cells by using intracellular flow cytometry. The results showed that expression of SAP in T cells, but not in B cells or NK cells, is required and sufficient for SAP-dependent antibody production and GC formation. These data provide a critical insight into the mechanism by which SAP regulates humoral immunity. They also help elucidate the basis of a severe human immunodeficiency.antibodies ͉ conditional knockout ͉ lymphocytes ͉ X-linked lymphoproliferative ͉ SH2D1A

SAP-Regulated T Cell–APC Adhesion and Ligation-Dependent and -Independent Ly108–CD3ζ Interactions

“…AlexaFluor 647-conjugated anti-SAP [clone 12C4, a kind gift from Dr. André Veillette (39)] was used to stained for 30 min.…”

Altered expression of signalling lymphocyte activation molecule (SLAM) family receptors CS1 (CD319) and 2B4 (CD244) in patients with systemic lupus erythematosus

“…Mutations in SH2D1A, the gene encoding SAP, are responsible for the primary immunodeficiency X-linked lymphoproliferative disease (XLP) in humans [10][11][12]. Studies using knock-out mice deficient in SAP and SLAM family receptors indicate that SLAM family receptors and SAP play an important role in T cell-mediated help for humoral immunity [13][14][15][16].…”

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

“…Consequently, SLAM receptors are capable of regulating either homotypic-or heterotypic-cell/cell interactions between immune cells. Through investigations of XLP patients and genetargeted mice, a common theme has emerged for SAP in regulating lymphocyte-lymphocyte contact, communicating signals necessary for lymphocyte differentiation and executing effector function: CD4 C T cell-B cell interactions in generating T FH cells, germinal centers, B cell isotype-switching and B cell memory; [14][15][16][17] thymocyte-thymocyte interactions instructing the development of NKT cells; [18][19][20] NK cell-haematopoietic target interactions controlling cytotoxicity [21][22][23] and effector CD8 T cell-B cell interactions modulating CD8…”