Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product

Pasquier, Benoit; Yin, Ling; Fondanèche, Marie-Claude; Relouzat, Francis; Bloch-Queyrat, Coralie; Lambert, Nathalie; Fischer, Alain; Basile, Geneviève de Saint; Latour, Sylvain

doi:10.1084/jem.20042432

Cited by 305 publications

(260 citation statements)

References 24 publications

Supporting

Mentioning

248

Contrasting

Unclassified

Order By: Relevance

“…This last observation suggested that the cd4-cre transgene was causing partial deletion of the sap gene in NK-T cells, in agreement with the fact that NK-T cells are derived from a CD4 ϩ CD8 ϩ T cell precursor (21). As reported (22)(23)(24), a severe reduction (Ϸ90%) of NK-T cell numbers was seen in conventional sap Ϫ/Ϫ mice (data not shown). In sap f l/f l ;lck-cre mice (Fig.…”

Section: Resultssupporting

confidence: 68%

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

Veillette

Zhang

Shi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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

show abstract

Section: Resultssupporting

confidence: 68%

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

Veillette

Zhang

Shi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…This hypothesis suggests that Va14i + thymocytes undergo 'agonist selection', which leads to the activated/ memory phenotype on mature iNKT cells without (known) exogenous antigen encounter [46]. Another feature of iNKT cell development that is far afield from conventional T cell development is the requirement for signaling lymphocyte activation molecule (SLAM)-associated protein signaling through the tyrosine kinase Fyn [48,49]. The Fyn signal is required before the TCR signal, as iNKT cell development is rescued in fyn -/-mice crossed with the iNKT cell TCR transgene [50].…”

Section: Discussionmentioning

confidence: 99%

Immediate antigen‐specific effector functions byTCR‐transgenic CD8⁺ NKT cells

Wingender¹,

Berg²,

Jüngerkes³

et al. 2006

Eur J Immunol

View full text Add to dashboard Cite

Only recently have natural antigens for CD1d-dependent, invariant Va14 + natural killer T (iNKT) cells been identified. Similar data for CD1d-independent and CD8 + NKT cell populations are still missing. Here, we show that the MHC class I-restricted CD8 + TCRtransgenic mouse lines OT-I, P14 and H-Y contain a significant proportion of transgenic CD8 + NK1.1 + T cells. In liver, most of NK1.1 + T cells express CD8aa homodimers. Transgenic NKT cells did not bind invariant Va14-to-Ja18 TCR rearrangement (Va14i)-specific CD1d/a-galactosylceramide tetramers and the frequency of iNKT cells was severely reduced. The activated cell surface phenotype and the distribution of transgenic NKT cells in vivo were similar to that reported for iNKT cells. The OT-I and P14 CD8 + NKT cells recognized their cognate antigen in the context of H2-K b and produced cytokines shortly after TCR stimulation. Importantly, transgenic NKT cells exerted immediate antigen-specific cytotoxicity in vitro and in vivo. Our results demonstrate the presence of transgenic CD8 + NKT cells in MHC class I-restricted TCR-transgenic animals, which are endowed with rapid antigen-specific effector functions. These data imply that experiments studying naive T cell function in TCR-transgenic animals should be interpreted with caution, and that such animals could be utilized for studying CD8 + NKT cell function in an antigen-specific manner.

show abstract

“…It has been well established that SAP is an essential adaptor due to its capacity to recruit FynT to SLAM and p85 of PI3 K to 2B4, respectively [9,10]. SAP is expressed in activated T, NK and NKT cells, as well as in germinal center B cells [11,12], and is indispensable for normal NKT cell development, generation of a proper Th2 response and Ig class switching in humans and mice [13][14][15][16][17][18]. In XLP patients, both EBV-infected B cells and EBVspecific CTL hyper-proliferate, although the underlying mechanism is still controversial.…”

Section: Introductionmentioning

confidence: 99%

Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

et al. 2007

View full text Add to dashboard Cite

Defective signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is responsible for the human X-linked lymphoproliferative syndrome. Defects in T helper 2, natural killer, natural killer T and B cells have been demonstrated in SAP-deficient humans and mice, and increased proliferation of CD8 + T cells has been observed. In the current study, we investigated the properties of CD8 + T cell proliferation and activation-induced cell death (AICD), using OT-I T cell receptor (TCR)-transgenic mice on either wild-type (WT) or SAP -/-background. Interestingly, we found that ovalbumin peptide-activated SAP -/-CD8 + T cells have lower AICD compared to their WT counterparts. Furthermore, the induction of p73, a key mediator of TCRinduced apoptosis through the mitochondrial apoptotic pathway, was significantly reduced at both the mRNA and protein levels in the activated mutant cells. Meanwhile, a reduced level of activated caspase 9 was observed in the mutant cells. We conclude that reduced AICD in activated SAP -/-CD8 + T cells is associated with impaired p73 induction, indicating that the initiation of the mitochondrial apoptotic pathway might be impaired. Our data demonstrate an intrinsic defect in SAP -/-CD8 + T cells and shed light on the increased responsiveness of CD8 + T cells in SAP -/-mice. IntroductionX-linked lymphoproliferative syndrome (XLP), an abnormal immune response to EBV infection characterized by fatal infectious mononucleosis, dys-gammaglobulinemia and B cell lymphoma, is caused by mutations in the SH2D1A gene, which encodes signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) [1][2][3][4]. The adaptor SAP binds with high affinity to tyrosine motifs in the cytoplasmic domain of SLAM family immune receptors, including SLAM (CD150), CD244, CD229, SLAMF6, SLAMF7 and CD84, suggesting that SAP functions are important in modulating signals initiated by the SLAM family receptors [5][6][7][8]. It has been well established that SAP is an essential adaptor due to its capacity to recruit FynT to SLAM and p85 of PI3 K to 2B4, respectively [9,10]. SAP is expressed in activated T, NK and NKT cells, as well as in germinal center B cells [11,12], and is indispensable for normal NKT cell development, generation of a proper Th2 response and Ig class switching in humans and mice [13][14][15][16][17][18]. In XLP patients, both EBV-infected B cells and EBVspecific CTL hyper-proliferate, although the underlying mechanism is still controversial. Previous studies with SAP -/-mice, performed by several laboratories including ours, showed an increased antigen-specific CD8 + T cell population and IFN-c production after infection with lymphocytic choriomeningitis virus (LCMV), murine c-herpesvirus 68 (MHV-68) and Toxoplasma gondii, but impaired Th2 cell differentiation and decreased IgG production [15,19,20]. In addition, we demonstrate that SAP -/-mice confer greater cytotoxic activity and increased proliferation of CD8 + T cells compared to WT mice, strongly suggesting that SAP fine-tunes th...

show abstract

Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product

Cited by 305 publications

References 24 publications

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

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

Immediate antigen‐specific effector functions byTCR‐transgenic CD8⁺ NKT cells

Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

Contact Info

Product

Resources

About

Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product

Cited by 305 publications

References 24 publications

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

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

Immediate antigen‐specific effector functions byTCR‐transgenic CD8+ NKT cells

Increased proliferation of CD8+ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

Contact Info

Product

Resources

About

Immediate antigen‐specific effector functions byTCR‐transgenic CD8⁺ NKT cells

Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death