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The Journal of Immunology, 2005, 174: 3153-3157.
Copyright © 2005 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Signaling Lymphocytic Activation Molecule-Associated Protein Controls NKT Cell Functions 1

Brian Chung*, Ala Aoukaty*, Jan Dutz{dagger}, Cox Terhorst{ddagger} and Rusung Tan2,*

Departments of * Pathology and Laboratory Medicine and {dagger} Medicine, British Columbia Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada; and {ddagger} Harvard Institute of Medicine, Boston, MA 02115


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
X-linked lymphoproliferative disease (XLP) is a fatal immunological disorder that typically manifests following EBV infection. XLP patients exhibit a number of immune defects including abnormal T, B, and NK lymphocyte function. These defects have been attributed to mutations of Src homology 2 domain-containing gene 1A (SH2D1A), the gene encoding signaling lymphocytic activation molecule-associated protein (SAP), an intracellular adaptor molecule expressed in lymphocytes. We have observed that SAP knockout (SAPKO) mice and humans with XLP have a complete lack of CD1d-restricted NKT cells. As expected, SAPKO mice injected with the NKT cell agonist, {alpha}-galactosylceramide failed to generate NKT cell IFN-{gamma} or IL-4. Furthermore, in contrast to wild-type littermates, SAPKO mice coinjected with OVA and {alpha}-galactosylceramide failed to mount OVA-specific CTL responses. These data suggest that an absence of NKT cells may underlie part of the immune dysregulation seen in SAPKO mice and in XLP patients.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
X-linked lymphoproliferative disease (XLP) 3 is a primary immunodeficiency disorder characterized by fulminant infectious mononucleosis and hemophagocytosis following primary EBV infection and in later stages, by chronic hypogammaglobulinemia, and non-Hodgkin’s B cell lymphoma (1). These complications are not mutually exclusive and other expressions of XLP disease have also been reported, notably aplastic anemia and systemic vasculitis. Regardless of the clinical presentation, the prognosis for XLP patients remains poor with affected males suffering substantial morbidity and mortality often before adulthood. A major breakthrough in understanding the immunopathogenesis of XLP occurred when mutations of the gene Src homology 2 (SH2) domain-containing gene 1A (SH2D1A) were identified to be responsible for disease (2, 3, 4). SH2D1A comprises four exons that encode signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), an adaptor molecule of 128 amino acids containing a single SH2 domain and a short C terminus. Many SH2D1A mutations, including stop codons, truncations and missense mutations all of which affect the SH2 domain, have been described in patients clinically diagnosed with XLP.

A role for SAP in lymphocyte regulation has been suggested by the uncontrolled proliferation of T and B cells seen during the clinical course of XLP disease (1) and by the observation that SAP knockout (SAPKO) mice generate abnormally large virus-specific CD8+ and CD4+ T cell populations following infection with lymphocytic choriomeningitis virus (LCMV) (5). Other evidence that SAP participates in lymphocyte regulation comes from the discoveries that SAP binds to the intracellular domains of SLAM (3) and 2B4 (6), two immune regulatory molecules primarily expressed on T cells and NK cells, respectively. Subsequent studies have also confirmed that interaction of SAP with SLAM mediates critical T cell signaling (7), that SAP-2B4 interactions underlie abnormal NK cell function in XLP (8, 9, 10), and that SAPKO mice have an inability to generate memory B cell responses (11).

Despite evidence of abnormal lymphocyte signaling and function in humans with XLP and in SAPKO mice, a role for SAP in NKT cells, a subset of regulatory lymphocytes, has not been described. NKT cells share some phenotypic characteristics with NK cells and activated or memory T cells (12) and thus might also be expected to express SAP. In addition, NKT cells are important regulators of immunity and autoimmunity in both mouse and human studies (12, 13). Moreover, Ho et al. (14) have recently reported that CD1d-restricted NKT cells act to regulate EBV-specific lymphocyte expansions, a possible link between NKT cell function and the large T cell expansions seen in XLP patients following EBV infection.

Therefore, we sought to determine a role for NKT cells in the immune dysregulation of SAPKO mice. To our surprise, we observed that SAPKO mice have a complete absence of CD1d-restricted NKT cells and that SAPKO mice injected with the potent NKT cell agonist, {alpha}-galactosylceramide ({alpha}-GalCer), fail to develop or activate CD1d-restricted NKT cells that produce IFN-{gamma} or IL-4. SAPKO mice were also unable to mount OVA-CTL responses when coinjected with OVA and {alpha}-GalCer. Finally, in contrast to healthy individuals, two patients with XLP lacked a population of CD1d-restricted NKT cells in their peripheral blood. These findings suggest that SAP is critical for normal CD1d-restricted NKT cell development and that the absence of CD1d-restricted NKT cells may underlie the immunological abnormalities observed in SAPKO mice and XLP patients.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Mice

C57BL/6 mice 6–8 wk of age were obtained from Charles River Laboratories. SAPKO mice backcrossed to a C57BL/6 background (5) were maintained in a specific pathogen-free facility in the animal care unit of the British Columbia Research Institute for Children’s & Women’s Health. SAP gene expression in C57BL/6 (wild-type (WT)) and SAP-deficient mice was confirmed by PCR and by immunoprecipitations/Western blots (data not shown). The care and use of these animals was approved by the Animal Care Committee, University of British Columbia.

Patient samples

XLP patient peripheral blood samples were obtained from two boys with a mutation within the second exon of SH2D1A (15). Control blood samples were obtained from healthy donors. The collection of samples was approved by the University of British Columbia Clinical Research Ethics Board and informed consent was obtained from all subjects before the collection of blood.

Flow cytometry, Abs, and tetramers

Sample data were collected using a FACSCalibur flow cytometer and analyzed with CellQuest (BD Biosciences). Anti-CD3-FITC, anti-TCRV{beta}8.1/8.2-FITC, anti-NK1.1-PE, IgG-PE, anti-B220-PerCP, anti-IFN-{gamma}-allophycocyanin, and anti-IL-4-allophycocyanin mAbs were purchased from BD Biosciences. Anti-CD8-FITC was purchased from Cedarlane Laboratories. PE-conjugated Kb-OVA254–267 tetramer was synthesized according to standard protocols. PE-conjugated CD1d unloaded and loaded with {alpha}-GalCer tetramer were a gift from S. Porcelli (Albert Einstein College of Medicine, Bronx, NY). For immunostaining, single cell suspensions of lymph nodes, spleen, liver, and thymus were resuspended in PBS containing 0.3% BSA and 0.2% Na3N. CD1d tetramer+ NKT cells were stained with loaded or unloaded CD1d tetramer for 60 min on ice followed by anti-TCRV{beta}8.1/8.2-FITC and anti-B220-PerCP for 30 min. NKT cells were stained with anti-NK1.1-PE, or IgG-PE and anti-CD3-FITC and anti-B220-PerCP for 30 min on ice. OVA-CTLs were stained with a PE-conjugated control tetramer or PE-conjugated Kb-OVA254–267 tetramer for 60 min on ice followed by anti-CD8-FITC and anti-B220-PerCP for 30 min.

Intracellular IFN-{gamma} and IL-4 staining

Mouse liver cells were isolated 2 h following a single i.p. injection of 4 µg of {alpha}-GalCer (Kirin Brewery). Liver cells were stained with CD1d tetramer as above and processed for intracellular cytokine staining according to the manufacturer’s protocol (Fixation/Permeablization kit with Golgistop; BD Biosciences). Cells were stained with anti-IFN-{gamma}-allophycocyanin or anti-IL-4-allophycocyanin for 30 min on ice.

OVA immunization

Mice were injected s.c. on days 1 and 8 with 2 µg of {alpha}-GalCer and 500 µg of chicken OVA grade VII (Sigma-Aldrich). PBLs were costained with anti-CD8 and Kb-OVA254–267 tetramers on day 14.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
SAPKO mice lack NKT cells

To determine a role for SAP in NKT cell function, lymphocytes from SAPKO mice and C57BL/6 littermates were stained with Abs to CD3 and NK1.1, surface molecules that mark the NKT cell population in this mouse strain (12). We found that the frequencies of NKT cells in the lymph node, spleen, liver, and thymus of SAPKO mice were significantly lower than those of C57BL/6 littermates suggesting that SAPKO mice lack NKT cells (Fig. 1A). However, although the coexpression of NK1.1 and CD3 has been used frequently to identify NKT cells, these surface molecules fail to exclusively identify CD1d-restricted NKT cells (16). Therefore, lymph node, spleen, liver, and thymus cells were costained with CD1d tetramer and Ab to TCRV{beta}8 (Fig. 1, B and C). These data confirmed that SAPKO mice have a complete absence of CD1d-restricted NKT cells.



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  		FIGURE 1. SAPKO mice lack NKT cells. CD3+/NK1.1+ and CD1d-restricted NKT cells (CD1d tetramer+/TCRV{beta}8.1/8.2+) are absent from the lymph node, spleen, liver, and thymus of SAPKO mice (SAPKO) compared with C57BL/6 littermates (control). Representative FACS plots indicate the frequency of CD3+/NK1.1+ (A) and CD1d-restricted NKT cells (B) in the indicated organs. The mean percentages of CD3+/NK1.1+ and CD1d-restricted NKT cells in SAPKO (n = 6) and control mice (n = 6) ±SEM are shown in (C), *p < 0.05.

 
SAPKO mice fail to generate NKT cell cytokines in response to {alpha}-GalCer

NKT cells are known to produce IFN-{gamma} and IL-4 rapidly upon activation and these responses are thought to be important for bridging innate and adaptive immunity (17, 18, 19, 20). Given the absence of CD1d-restricted NKT cells, we anticipated that these cytokine responses might be absent in SAPKO mice. To test this hypothesis, SAPKO mice were given i.p. injections of {alpha}-GalCer and the liver population of CD1d-restricted NKT cells was assayed for production of IFN-{gamma} and IL-4. These cytokines are normally produced rapidly upon {alpha}-GalCer administration (18, 19). Two hours after a single injection of {alpha}-GalCer, we observed no production of IFN-{gamma} or IL-4 from the hepatic CD1d-restricted NKT cells of SAPKO mice (Fig. 2). In fact, no CD1d-restricted NKT cells were seen in SAPKO mice. In contrast, CD1d-restricted liver cells from C57BL/6 mice produced significant amounts of IFN-{gamma} (mean 79.4 ± 3.8%) and IL-4 (mean 26.7 ± 5.3%) following {alpha}-GalCer administration. These data indicate that SAPKO mice are unable to mount a rapid NKT cell cytokine response characterized by production of IFN-{gamma} and IL-4.



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  		FIGURE 2. SAPKO mice fail to generate NKT cell cytokines in response to {alpha}-GalCer. Hepatic C57BL/6 (control) and SAPKO CD1d-restricted NKT cells (CD1d tetramer+/TCRV{beta}8+) were isolated 2 h following i.p. injection of {alpha}-GalCer and the proportion of IFN-{gamma} (A) and IL-4 (B) secreting cells was determined.

 
NKT-dependent Ag-specific CTL proliferation is defective in SAPKO mice

NKT cells are functionally important for the generation and regulation of Ag-specific T cell responses. For example, CD1d-restricted NKT cells are known to regulate LCMV-induced cytokine production as well as the magnitude of the cell-mediated immune response to an acute viral infection (21). As well, activation of NKT cells by {alpha}-GalCer at the time of OVA immunization results in substantial OVA-specific CTL expansion (22). To determine whether the absence of NKT cells in SAPKO mice would affect activation or proliferation of Ag-specific CTL, both SAPKO and C57BL/6 mice were coinjected with OVA and {alpha}-GalCer twice and the OVA-CTL expansion was measured at day 14 using Kb-OVA254–267 tetramers. Immunization with OVA and {alpha}-GalCer produced minimal OVA-specific CTL in SAPKO mice whereas WT mice demonstrated significant expansions (Fig. 3). C57BL/6 mice immunized with a control for {alpha}-GalCer (vehicle alone) and SAPKO mice injected with OVA but not {alpha}-GalCer also failed to produce significant OVA-CTL expansions. Moreover, SAPKO and C57BL/6 mice immunized with OVA and CFA produced similar CTL expansions demonstrating that the defective responses seen in {alpha}-GalCer-injected SAPKO mice were not due to an intrinsic defect in production of Ag-specific CTL. These data indicate that activated CD1d-restricted NKT cells promote the generation of Ag-specific CTL and that SAPKO mice lack the ability to generate CTL in response to immunized Ag and NKT cell agonist.



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  		FIGURE 3. NKT cell-dependent Ag-specific CTL proliferation is impaired in SAPKO mice. Representative FACS plots indicate the frequency of OVA-CTL (Kb-OVA254–267 tetramer+/CD8+) in the peripheral blood of C57BL/6 (control) and SAPKO littermates immunized with OVA and vehicle (control for {alpha}-GalCer), CFA, or {alpha}-GalCer (A). The mean frequency ± SEM of Kb-OVA254–267 tetramer+/CD8+ peripheral blood monocytes of immunized control (n = 3) and SAPKO (n = 3) is shown in (B), *, p < 0.004.

 
CD1d-restricted NKT cells are absent in XLP

To determine whether NKT cells are absent in XLP patients, two individuals with mutations in the second exon of SAP that are known to produce the clinical phenotype of XLP (15) were studied for the presence of NKT cells. CD1d-restricted NKT cells are normally present at a low but consistent frequency in the peripheral blood of healthy individuals (23, 24). PBMC from the XLP patients and from eight healthy controls were stained with CD1d tetramer and anti-CD3 to determine the frequency of NKT cells (Fig. 4). A small but reproducible population of CD1d tetramer+/CD3+ cells was present in the blood of all controls (mean 0.024 ± 0.005% SEM). These frequencies are similar to those previously reported (23, 24). In contrast, neither XLP individual had any evidence of NKT cells in the peripheral blood.



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  		FIGURE 4. CD1d-restricted NK T cells are absent in XLP patients. Representative FACS plots compare the frequency of CD1d-restricted NKT cells (CD1d tetramer+/CD3+) in the peripheral blood of an XLP patient and healthy control (A). Healthy controls (n = 8, •) in contrast to XLP patients (n = 2, {blacksquare}) have an infrequent but significant population of NKT cells in the peripheral blood (B). The mean frequencies are represented by a horizontal bar, *, p < 0.003.

 
The findings above indicate that SAPKO mice and individuals with XLP lack CD1d-restricted NKT cells. The broad importance of NKT cells for immune regulation suggests that the complete absence of this lymphocyte subset underlies some if not many of the pathological immune responses seen in XLP and in SAPKO mice. For example, NKT cells bridge innate and adaptive responses by rapidly activating NK cells (20) and by fostering dendritic cell maturation (25, 26, 27) and the ability to generate optimal OVA-specific CTL responses with concomitant {alpha}-GalCer administration has been directly attributed to the effect of NKT cells on dendritic cell maturation (22). Furthermore, SAPKO mice infected with LCMV are unable to generate virus-specific memory humoral responses (11) and the failure to generate long-lived plasma cells may reflect a dependence of B cells on NKT cell factors (28). The requirement for SAP in the development of NKT cells may be related to the src family kinase, FynT as mice deficient in FynT kinase do not develop CD1d-dependent NKT cells (29) and SAP has been shown to be critical for mediating recruitment of FynT to the SLAM receptor in T cells (30, 31). In addition, SAPKO mice have been shown to harbor defects in the development of Th2 responses (5) and mice engineered to lack a FynT kinase binding site on SAP exhibit deficiencies in both IL-4 and IL-13 production (32). These latter defects were attributed to an inability of mutated SAP to bridge FynT-SLAM association. Therefore, the inability of SAP-deficient mice to generate normal Th2 responses may be related to the inability of FynT kinase to associate with SLAM family receptors thus leading to abnormal NKT development.

With regard to the clinical presentation of XLP, we hypothesize that in the absence of the NKT cell help that is necessary for a rapid NK cell response and for dendritic cell maturation, a suboptimal antiviral cellular response occurs. Viral replication would therefore proceed through its early stages unchecked, allowing for a chronic viral state to develop. This model is supported by our clinical observations that boys with XLP have detectable EBV viremia throughout the course of their disease. Viral infection that is not swiftly constrained may lead to the chronic stimulation of virus-specific CD8+ T cells that are unable to efficiently clear virus-infected cells, as in the case of perforin (33) or IFN-{gamma}-deficient mice (34).

In conclusion, we show that SAPKO mice and XLP patients have a complete lack of CD1d-restricted NKT cells. The absence of NKT cells may underlie the virus-induced immune pathology seen in SAPKO mice and humans with XLP and SAP must be required for the development of NKT cells.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Acknowledgments
 
We thank Henry Pabst, Anne Junker, and Kirk Schultz for providing patient samples. We thank Steven Porcelli for use of the CD1d tetramer. These experiments were supported by the Canadian Institutes of Health Research.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 A.A. was supported by the Michael Smith Foundation for Health Research and B.C. by a David Hardwick Studentship. R.T. was a Peter Wall Institute for Advanced Studies Scholar. Back

2 Address correspondence and reprint requests to Dr. Rusung Tan, Department of Pathology and Laboratory Medicine, British Columbia Children’s Hospital, 4480 Oak Street, Room 2G5, Vancouver, British Columbia, Canada, V6H 2V4. E-mail address: roo{at}interchange.ubc.ca Back

3 Abbreviations used in this paper: XLP, X-linked lymphoproliferative disease; SH2, Src homology 2; SH2D1A, SH2 domain-containing gene 1A; SLAM, signaling lymphocytic activation molecule; SAP, SLAM-associated protein; SAPKO, SAP knockout; LCMV, lymphocytic choriomeningitis virus; {alpha}-GalCer, {alpha}-galactosylceramide; WT, wild type. Back

Received for publication November 11, 2004. Accepted for publication January 15, 2005.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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