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The Journal of Immunology, 2007, 179, 3397 -3401
Copyright © 2007 by The American Association of Immunologists, Inc.
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Cutting Edge: Syntaxin 11 Regulates Lymphocyte-Mediated Secretion and Cytotoxicity1

Laura N. Arneson2, Adipong Brickshawana, Colin M. Segovis, Renee A. Schoon, Christopher J. Dick and Paul J. Leibson

Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Little is known about the regulatory roles of specific soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in cytotoxic lymphocytes. Recent information suggests that mutations in the SNARE protein syntaxin 11 result in a form of familial hemophagocytic lymphohistiocytosis (FHL). Because genetic abnormalities in key granule components (e.g., perforin) or in regulators of secretion (e.g., Munc13–4) underlie the other identified forms of FHL, we assessed whether syntaxin 11 might also serve a related regulatory role. We determined that syntaxin 11 is expressed in NK cells and activated CTLs and is located in discrete membrane-associated structures in the cytoplasm. Enhanced expression of syntaxin 11 augments the secretion and killing of tumor targets, and suppression of syntaxin 11 expression inhibits these functions. Our data identify and characterize a role for syntaxin 11 in granule exocytosis and in the generation of cell-mediated killing. These results also provide new insights on the mechanisms of hemopoietic dysregulation in FHL.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Familial hemophagocytic lymphohistiocytosis (FHL)3 is a syndrome characterized by overactivation of the immune system. Patients with FHL present with an increased inflammatory response involving hypersecretion of proinflammatory cytokines. However, despite this global hyperstimulation, impaired function of NK cells and CTLs is a hallmark feature of FHL (1, 2).

Both NK cells and CTLs initiate apoptosis of targets through granule secretion, and this cell-mediated killing is important for the contraction of the immune system after activation. Impairment of this activation-induced cytotoxicity results in the prolonged secretion of cytokines and the hyperactivation of phagocytes that are believed to be the cause of the dysregulation of the immune system in FHL. All known genetic defects that result in FHL result in impaired NK cell and CTL function. FHL type 2 is caused by defects in the pore-forming protein perforin (3). Mutations in the exocytic machinery (e.g., Munc13-4 and Rab27a) have also been shown to result in FHL by impairing the ability to deliver granules correctly (4, 5).

Most recently, mutations in the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin 11 have been shown to be responsible for a specific subtype of FHL (6, 7). Surprisingly, in contrast to other known causes of FHL, syntaxin 11 is not known to be involved in the secretory machinery or the cytotoxic arsenal of NK cells or CTLs (6, 8). Moreover, it is unclear from initial characterizations whether syntaxin 11 is even present in NK cells or CTLs. Thus, it has been hypothesized that FHL type 4 may be the result of indirect dysregulation of NK cells by other cell types that do express syntaxin 11 (6).

The SNARE proteins, including syntaxin 11, facilitate fusion in intracellular membrane trafficking events (9). Unlike the other syntaxins, syntaxin 11 does not contain a C-terminal transmembrane domain (10); rather, it is believed to be associated with membranes by palmitoylation of cysteine residues or by interaction with other SNARE proteins (8, 11, 12).

In this study we demonstrate that syntaxin 11 is, in fact, expressed in NK cells and CTLs and we define a new function for this SNARE protein in the regulation of granule exocytosis and the generation of cell-mediated cytotoxicity. These results are also consistent with the syntaxin 11 dysfunction in cytotoxic cells being directly responsible for the defects observed in FHL type 4.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Reagents, cells, antibodies

The tumor cell lines and Abs are as previously described (13). NK cells and CD8+ T cells were fractionated from freshly isolated PBL using the RosetteSEP reagents and protocol from Stem Cell Technologies. Clonal nontransformed human NK and CTL cell lines were generated and passaged as previously described (14). The anti-syntaxin 11 mAb was purchased from BD Biosciences Transduction Laboratories.

Recombinant vaccinia

The sequence for syntaxin 11 was inserted into the previously described pSP11.F plasmid and incorporated into vaccinia by homologous recombination (13, 15).

Cytotoxicity assays

The 51Cr-release assays were done as described (14). Lytic units (LU) per 106 cells were calculated on the basis of 20% cytotoxicity (16). After calculation of the LU for each treatment group, the results are expressed as a percentage of control.

Cell stimulations, immunoprecipitations, cell fractionations, and immunoblot analyses

Cell stimulations, protein immunoprecipitations, cell fractionations, and immunoblot analyses were done as previously described (17, 18).

Stimulation and measurement of secretion

Stimulations and secretions were as previously described (19). Specific granule exocytosis was determined as a percentage of the total cellular enzyme content. Results for each treatment group are expressed as a percentage of control.

Syntaxin 11 suppression

The syntaxin 11-specific small interfering RNA (siRNA) were obtained as a Dharmacon SMARTpool containing four constructs. NK cells were nucleofected with the constructs using the Amaxa Cell line Nucleofector kit V, program O-17. Cells were nucleofected with 300 pmol of the indicated siRNA.

Fluorescent confocal microscopy

Cell preparations were done using a modification of a previously published method (20).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
Syntaxin 11 is expressed in discrete membrane-associated structures in the cytoplasm of NK cells and CTLs.

To establish whether the role of syntaxin 11 on NK cell function is due to a direct effect on NK cells, we sought to determine the expression pattern for syntaxin 11 in cytotoxic lymphocytes. CD16+ NK cells and CD8+ T cells were fractionated from freshly isolated PBLs. As noted in Fig. 1A, human NK cells express syntaxin 11. To ensure that contaminating accessory cells were not the source of the syntaxin 11, we next analyzed clonally derived, nontransformed, homogeneous pure populations of human NK cells for their expression of syntaxin 11. Syntaxin 11 was detected in all NK clones tested (Fig. 1B). In contrast, freshly isolated T cells had barely detectable levels of syntaxin 11 protein in repeated experiments (Fig. 1A). Analyses of clonally derived, pure populations of human CD8+ T cells that had been exposed to PHA and IL-2 and have cytotoxic capability indicated that some CTL clones began to express syntaxin 11 at levels comparable to those of NK clones, whereas others did not (Fig. 1B).


Figure 1
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  		FIGURE 1. Syntaxin 11 expression in human NK cells and activated CTLs. A, Freshly isolated human mononuclear cells were fractionated into CD16+ NK cells (90% purity) and CD8+ T cells (96% purity). Cell lysates were prepared from these subpopulations of lymphocytes and from an EBV-transformed B cell line (EBV-B cells) and the leukemic cell line K562. One hundred micrograms of protein from each cell lysate was resolved by SDS-PAGE, transferred to a membrane, and then probed serially with syntaxin 11-specific mAb (upper panel) and ZAP70-specific antisera (lower panel). B, Cell lysates were prepared from three different clonal populations of nontransformed human NK cells, two different clonal population of nontransformed human CTLs, and the T cell tumor line Jurkat. One hundred micrograms of protein from each cell lysate was resolved and blotted as above. C, A clonal population of human NK cells was stimulated for the indicated time (in minutes) with K562 tumor cells (E:T = 2:1). Lysates from each reaction mixture were fractionated into cytosolic-associated (C) and membrane-associated (M) proteins. Resolved proteins were probed serially with syntaxin 11-specific mAb (upper panel), ERK2-specific antisera (middle panel), and linker for activation of T cells (LAT)-specific antisera (lower panel). D, A clonal population of human NK cells was infected with recombinant vaccinia encoding FLAG-tagged syntaxin 11. After fixation and permeabilization, the cells were stained with anti-FLAG mAb followed by goat anti-mouse Ig-Alexa Fluor 488 and 4',6-diamidino-2-phenylindole (DAPI) (for nuclear staining). Images were captured by confocal microscopy.

 
Syntaxin is an atypical SNARE protein in that it lacks a transmembrane region (10). Yet, consistent with previous reports (6, 8, 12), we found that syntaxin 11 is tightly associated with the membrane fractions of secretory cells (Fig. 1C). Also, consistent with other reports (8, 12), syntaxin 11 is found in discrete intracellular structures rather than at the plasma membrane (Fig. 1D).

Syntaxin 11 regulates NK cell-mediated cytotoxicity

To determine whether syntaxin 11 plays a role in modulating cell-mediated cytotoxicity, we examined the effect of altering expression levels of the protein. Expression of syntaxin 11 in cytotoxic lymphocytes was enhanced using recombinant vaccinia expressing a FLAG-tagged construct of the protein. Infection with the recombinant vaccinia resulted in levels of FLAG-tagged syntaxin 11 that were approximately equal to those of endogenous syntaxin 11 (Fig. 2A). Enhanced expression of syntaxin 11 in freshly isolated human NK cells increased the killing of the NK-sensitive tumor targets 721 and K562 (Fig. 2B). Similarly, enhanced expression of syntaxin 11 in multiple clonal populations of pure, nontransformed human NK cells augmented their cytotoxicity (Figs. 2, C and D). Enhanced expression of syntaxin 11 in CTLs also enhanced their ability to mediate cellular cytotoxicity (data not shown).


Figure 2
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  		FIGURE 2. Enhanced expression of syntaxin 11 in human NK cells increases NK cell-mediating cytotoxicity. A, Clonal populations of human NK cells and human CTLs were infected with control vaccinia (WR) or recombinant vaccinia encoding FLAG-tagged syntaxin 11 (Syn 11). Proteins from cell lysates were resolved by SDS-PAGE, transferred to a membrane, and then probed with syntaxin 11-specific mAb. B, A freshly isolated population of human NK cells (82% purity) was infected with either control vaccinia (WR) or recombinant vaccinia encoding syntaxin 11 (Syn11). The cells were then incubated with 51Cr-labeled 721 cells or 51Cr-labeled K562. LU per 106 cells were calculated for each treatment group (for each bar from left to right: 19.9, 37.7, 20.4, and 33.5). Results are expressed as a percentage of the control WR infections. Results are representative of three independent experiments. C, Cells from three different clonal populations of human NK cells were infected as described above and then incubated with 51Cr-labeled P815 cells and anti-Fc receptor (anti-FcR) mAb. LU for each bar from left to right: 28, 53, 17.2, 24.6, 16.8, and 29.2. D, A clonal population of human NK cells was infected as described above and assessed for cytotoxicity against either K562 cells, 721 cells, or P815 cells and anti-NKG2D. LU for each bar from left to right: 68.9, 121, 17.8, 29, 10.9, and 18.4.

 
To determine the effect of decreasing expression of syntaxin 11, the expression of the protein was specifically disrupted using siRNA. Syntaxin 11-specific siRNA decreased endogenous syntaxin 11 levels in either freshly isolated NK cells or IL-2-activated NK cells (Fig. 3A). The suppression in different experiments ranged from 44 to 92%. In each case, suppression of syntaxin 11 in freshly isolated human NK cells, IL-2-activated NK cells, or clonal pure populations of nontransformed NK cells resulted in decreased cytotoxicity against a variety of NK-sensitive targets (Fig. 3, B and C). The partial, rather than complete, inhibition of killing may reflect the activity of the residual syntaxin 11 or possible partial redundancies between syntaxin 11 and other regulators of cell-mediated cytotoxicity. The latter explanation might also underlie the somewhat later age of onset of FHL due to syntaxin mutations as compared with patients with perforin mutations (6, 7). However, recent work reveals that the age of onset of FHL-type pathologies can be strongly influenced by exposure to specific types of infectious agents (21).


Figure 3
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  		FIGURE 3. Suppression of syntaxin 11 expression in human NK cells inhibits NK cell-mediated cytotoxicity. A, Freshly isolated NK cells were nucleofected with the indicated siRNA (Neg, Negative; Syn 11, syntaxin 11) and then incubated for 72 h in the absence or presence of IL-2. Resolved cell proteins were probed serially for syntaxin 11 (Syn 11) and ZAP70 expression. B, Freshly isolated NK cells treated as above were assayed for cytotoxicity against either 721 or K562 target cells. LU for each bar from left to right: 25.9, 15.3, 25.1, 20.0, 98.7, 56.1, 110, and 74. Results are representative of two independent experiments. C, A clonal population of human NK cells was nucleofected with the indicated siRNA and then incubated for 48 h. Cells were assayed for cytotoxicity against the indicated targets. LU for each bar from left to right: 44, 33, 110, 76, 57, 24, 18, and 8.4. Results are representative of two independent experiments.

 
Syntaxin 11 modulates NK cell granule exocytosis

The generation of effective cell-mediated killing is initiated by a well-characterized cascade of early signaling events such as the sequential activation of Src and Syk family tyrosine kinases. Suppression of syntaxin 11 has no effect on these proximal signaling events as measured by the tyrosine phosphorylation of multiple intracellular substrates (Fig. 4A). We proceeded to determine whether syntaxin 11 would instead be regulating the distal events required for the terminal release of granules containing apoptosis-inducing molecules such as granzymes and perforin. Consistent with the data on cell-mediated killing, enhanced expression of syntaxin 11 increased Fc receptor-initiated secretion (Fig. 4B) whereas syntaxin 11 suppression inhibited this granule exocytosis (Fig. 4C). Notably, using the pharmacologic secretagogues 12-O-tetradecanoylphorbol-13-acetate (TPA) and ionomycin allowed us to bypass the proximal signaling events to determine whether syntaxin 11 affected the distal secretory events. Secretion induced by protein kinase C-activating phorbol ester and the calcium ionophore ionomycin was again increased by enhanced expression of syntaxin 11 (Fig. 4B) and decreased by syntaxin 11 suppression (Fig. 4C). These results suggest a distal role for syntaxin 11 in the regulation of granule release from cytotoxic lymphocytes.


Figure 4
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  		FIGURE 4. Syntaxin 11 regulates NK cell granule exocytosis. A, A clonal population of human NK cells was nucleofected with the indicated siRNA (Neg, Negative). Cells from each treatment group were stimulated with anti-Fc receptor (FcR). Cell lysates were resolved by SDS-PAGE, transferred to a membrane, and then probed with anti-phosphotyrosine (p-tyr) mAb. Syn11, Syntaxin 11. B, A clonal population of human NK cells was infected with either control vaccinia (WR) or recombinant vaccinia encoding syntaxin 11. Cells from each treatment group were then stimulated for 4 h with the indicated concentration of plate-bound anti-FcR mAb or with 12-O-tetradecanoylphorbol-13-acetate (TPA) and ionomycin. Specific granule release for each bar from left to right: 11.3, 15.3, 7.4, 11.1, 13.7, and 17.3. C, A clonal population of NK cells was nucleofected with the indicated siRNA and then incubated for 48 h. Cell from each treatment group were then stimulated as indicated and granule release was determined. Specific granule release for each bar from left to right: 8.9, 6.9, 7.6, 5.6, 6.9, and 3.0. The results are representative of three independent experiments.

 
Recent reports have highlighted the complexity of the secretory apparatus in cytotoxic lymphocytes. Centrosome polarization plays a key role in delivering secretory granules to sites next to the plasma membrane (22). In addition, regulators of secretion such as Munc13-4 can initially reside in endosomal structures separate from the cytotoxic lysosomal granules containing perforin and granzymes (23). It remains to be determined in which of the heterogeneous intracellular vesicular compartments syntaxin 11 resides and functions. Earlier reports highlight the possibility that syntaxin 11 occupies intermediate compartments influencing vesicular transport between endosomal structures and the trans-Golgi network (8, 12). SNAP-23 has been identified as one potential binding partner for syntaxin 11 (12), but others may also exist. These reports, taken together with our data, suggest that syntaxin 11 in NK cells and activated CTLs may regulate, during the development of cell-mediated cytotoxicity, the events controlling vesicle movement from the interior of the cell rather than the terminal steps influencing granule fusion with the plasma membrane. Our results also suggest that the pathologies observed in FHL type 4 are likely due to alterations in syntaxin 11-dependent processes directly in cytotoxic lymphocytes.

After this paper was submitted, we became aware of an interesting report by Bryceson et al. (24) in which analysis of cells from patients with defects in syntaxin 11 further demonstrates the importance of this protein to normal cytotoxic function.


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


   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 This research was supported by the Mayo Foundation and by National Institutes of Health Grant CA47752. Back

2 Address correspondence and reprint requests to Dr. Laura N. Arneson, Department of Immunology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. E-mail address: lnarneson{at}yahoo.com Back

3 Abbreviations used in this paper: FHL, familial hemophagocytic lymphohistiocytosis; LU, lytic unit; siRNA, small interfering RNA; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor. Back

Received for publication May 29, 2007. Accepted for publication July 16, 2007.


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

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