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1.  Mapping a Dynamic Innate Immunity Protein Interaction Network Regulating Type I Interferon Production 
Immunity  2011;35(3):426-440.
SUMMARY
To systematically investigate innate immune signaling networks regulating production of type I interferon, we analyzed protein complexes formed after microbial recognition. Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions; 21% of interactions were modulated by RNA, DNA, or LPS. Overexpression and depletion analyses identified 22 unique genes that regulated NF-κB and ISRE reporter activity, viral replication, or virus-induced interferon production. Detailed mechanistic analysis defined a role for mind bomb (MIB) E3 ligases in K63-linked ubiquitination of TBK1, a kinase that phosphorylates IRF transcription factors controlling interferon production. Mib genes selectively controlled responses to cytosolic RNA. MIB deficiency reduced antiviral activity, establishing the role of MIB proteins as positive regulators of antiviral responses. The HI5 provides a dynamic physical and regulatory network that serves as a resource for mechanistic analysis of innate immune signaling.
doi:10.1016/j.immuni.2011.06.014
PMCID: PMC3253658  PMID: 21903422
2.  NEMO Binds Ubiquitinated TANK-Binding Kinase 1 (TBK1) to Regulate Innate Immune Responses to RNA Viruses 
PLoS ONE  2012;7(9):e43756.
RIG-I-like receptors (RLR) are intracellular sensors utilized by nearly all cell types for recognition of viral RNA, initiation of antiviral defense, and induction of type I interferons (IFN). TBK1 is a critical kinase implicated in RLR-dependent IFN transcription. Posttranslational modification of TBK1 by K63-linked ubiquitin is required for RLR driven signaling. However, the TBK1 ubiquitin acceptor sites and the function of ubiquitinated TBK1 in the signaling cascade are unknown. We now show that TBK1 is ubiquitinated on residues K69, K154, and K372 in response to infection with RNA virus. The K69 and K154 residues are critical for innate antiviral responses and IFN production. Ubiquitinated TBK1 recruits the downstream adaptor NEMO through ubiquitin binding domains. The assembly of the NEMO/TBK1 complex on the mitochondrial protein MAVS leads to activation of TBK1 kinase activity and phosphorylation of the transcription factor, interferon response factor 3. The combined results refine current views of RLR signaling, define the role of TBK1 polyubiquitination, and detail the mechanisms involved in signalosome assembly.
doi:10.1371/journal.pone.0043756
PMCID: PMC3445589  PMID: 23028469
3.  Encephalitogenic T cells that stably express both T-bet and RORγt consistently produce IFNγ but have a spectrum of IL-17 profiles 
Journal of neuroimmunology  2009;215(1-2):10-24.
Th1/Th17 cells, secreting both IFNγ and IL-17, are often associated with inflammatory pathology. We cloned and studied the cytokine phenotypes of MBP-specific, TCR-identical encephalitogenic CD4+ cells in relationship to Th1- and Th17-associated transcription factors T-bet and RORγt. IFNγ-producing cells could be sub-divided into those that are T-bet+/RORγt− and those that are T-bet+/RORγt+. The latter comprises a spectrum of phenotypes, as defined by IL-17 production, and can be induced to up-regulate IL-23R with IL-12 or IL-23. The former, bona fide Th1 cells, lack IL-23R expression under all conditions. In vivo, T-bet+/RORγt− and T-bet+/RORγt+ clones induce EAE equally well.
doi:10.1016/j.jneuroim.2009.07.007
PMCID: PMC2761534  PMID: 19692128
Th1/Th17 cells; Inflammation; Cytokines; Transcription factors; EAE/MS
4.  PKC phosphorylation of TRAF2 mediates IKKα/β recruitment and K63-linked polyubiquitination 
Molecular cell  2009;33(1):30-42.
Summary
Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is a key mediator in TNF signaling. Previous studies suggested that TRAF2 functions as an adaptor in the NF-κB and AP-1 pathways. However, the precise molecular mechanisms by which TRAF2 relays signals are unknown. We previously reported that TRAF2 is phosphorylated following TNF stimulation and now identify the PKC kinases responsible for phosphorylation. Phosphorylated TRAF2 facilitates recruitment of IKKα and IKKβ to the TNF receptor. Phosphorylation also determines K63-linked polyubiquitination of TRAF2 at lysine 31. TRAF2 K63-linked ubiquitination contributes to associations with TAB2/3 and activation of the downstream IKK and JNK kinases. The combined data reveal that phosphorylation of TRAF2 plays a critical role in TNF signaling by directing the IKK complex to the membrane, promoting TRAF2 K63-linked ubiquitination, and positioning the IKKα and IKKβ chains with the TAK1/TAB kinase.
doi:10.1016/j.molcel.2008.11.023
PMCID: PMC2643372  PMID: 19150425
5.  HOMEOSTATIC INTERACTIONS BETWEEN MEKK3 AND TAK1 INVOLVED IN NF-κB SIGNALING 
Cellular signalling  2008;20(4):705-713.
Several members of the mitogen-activated protein kinase kinase kinase (MAP3K) family including MEKK3 and TGFβ-activating kinase (TAK1) play nonredundant roles in activation of the NF-κB transcription factor. However, the mechanism by which MEKK3 mediates NF-κB signaling is not fully understood. In this report we investigate the association of murine MEKK3 with other proteins and their roles in NF-κB activation. Using tandem affinity purification TAK1 was identified as an endogenous protein that interacts with MEKK3. MEKK3-TAK1 interactions were confirmed by fluorescence resonance energy transfer and coimmunoprecipitation. MEKK3-TAK1 complexes contain non-phosphorylated forms of both molecules. Expression of non-phosphorylated TAK1 interferes with MEKK3 phosphorylation and NF-κB reporter activity induced by transient MEKK3 expression or TNFα stimulation. Addition of TAB1 facilitates TAK1 autophosphorylation and reverses the inhibitory effects of TAK1 on MEKK3 phosphorylation and NF-κB signal transduction in human 293 cells and TAK1 deficient mouse embryonic fibroblasts. The data provide insights into the homeostatic interactions that maintain basal NF-κB levels by holding the enzymes MEKK3 and TAK1 in their inactive state.
doi:10.1016/j.cellsig.2007.12.007
PMCID: PMC2362106  PMID: 18206350
TAK1; TAB1; MEKK3; NF-κB regulation; TNFα signaling; tandem affinity purification
6.  Heterogeneity of EAE mediated by multiple distinct T-effector subsets 
Journal of neuroimmunology  2007;192(1-2):3-12.
Both TH1 and TH17 lymphocytes are implicated in inducing EAE. In mice lacking IFNγ, TH17 are assumed to be the subset responsible for inflammation induction. Here, we demonstrate that IFNγ KO mice have two additional effector subsets, one that up-regulates TH17-associated pro-inflammatory genes, but does not make IL-17 protein, and a second that utilizes IL-12-related elements of the TH1 pathway in an IFNγ-independent manner. In vivo, these two subsets induce demonstrably different disease. By using homogeneous T cell lines, we can dissect the population of autoimmune effector cells, and demonstrate the multiplicity of pro-inflammatory pathways important in disease processes.
doi:10.1016/j.jneuroim.2007.09.031
PMCID: PMC2190732  PMID: 17976744
autoimmune encephalomyelitis; inflammation; effector T cell subsets; IL-17; IFNγ
7.  Phosphatase RNAi screen in mouse astrocytes identifies new regulators of NF-κB signaling 
Molecular cell  2006;24(4):497-509.
Summary
Regulation of NF-κB activation is controlled by a series of kinases, however the roles of phosphatases in regulating this pathway are poorly understood. We report a systematic RNAi screen of phosphatases that modulate NF-κB activity. Nineteen of 250 phosphatase genes were identified as regulators of NF-κB signaling in astrocytes. RNAi selectively regulates endogenous chemokine and cytokine expression. Co-immunoprecipitation identified associations of distinct protein phosphatase 2A core or holoenzymes with the IKK, NF-κB, and TRAF2 complexes. Dephosphorylation of these complexes leads to modulation of NF-κB transcriptional activity. In contrast to IKK and NF-κB, TRAF2 phosphorylation has not been well elucidated. We show the Thr117 residue in TRAF2 is phosphorylated following TNFα stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity. These results provide direct evidence for TNF-induced TRAF2 phosphorylation and demonstrate that phosphorylation is regulated at multiple levels in the NF-κB pathway.
doi:10.1016/j.molcel.2006.10.015
PMCID: PMC2572259  PMID: 17188031
8.  Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor 
The Journal of Experimental Medicine  2005;201(7):1037-1044.
Although certain chemokines and their receptors guide homeostatic recirculation of T cells and others promote recruitment of activated T cells to inflammatory sites, little is known of the mechanisms underlying a third function, migration of Foxp3+ regulatory T (T reg) cells to sites where they maintain unresponsiveness. We studied how T reg cells are recruited to cardiac allografts in recipients tolerized with CD154 monoclonal antibody (mAb) plus donor-specific transfusion (DST). Real-time polymerase chain reaction showed that intragraft Foxp3 levels in tolerized recipients were ∼100-fold higher than rejecting allografts or allografts associated with other therapies inducing prolonged survival but not tolerance. Foxp3+ cells were essential for tolerance because pretransplant thymectomy or peritransplant depletion of CD25+ cells prevented long-term survival, as did CD25 mAb therapy in well-functioning allografts after CD154/DST therapy. Analysis of multiple chemokine pathways showed that tolerance was accompanied by intragraft up-regulation of CCR4 and one of its ligands, macrophage-derived chemokine (CCL22), and that tolerance induction could not be achieved in CCR4−/− recipients. We conclude that Foxp3 expression is specifically up-regulated within allografts of mice displaying donor-specific tolerance, that recruitment of Foxp3-expressing T reg cells to an allograft tissue is dependent on the chemokine receptor, CCR4, and that, in the absence of such recruitment, tolerizing strategies such as CD154 mAb therapy are ineffectual.
doi:10.1084/jem.20041709
PMCID: PMC2213137  PMID: 15809349
9.  Inflammatory Chemokine Transport and Presentation in HEV 
The Journal of Experimental Medicine  2001;194(9):1361-1374.
Interstitial fluid is constantly drained into lymph nodes (LNs) via afferent lymph vessels. This conduit enables monocyte-derived macrophages and dendritic cells to access LNs from peripheral tissues. We show that during inflammation in the skin, a second recruitment pathway is evoked that recruits large numbers of blood-borne monocytes to LNs via high endothelial venules (HEVs). Inhibition of monocyte chemoattractant protein (MCP)-1 blocked this inflammation-induced monocyte homing to LNs. MCP-1 mRNA in inflamed skin was over 100-fold upregulated and paralleled MCP-1 protein levels, whereas in draining LNs MCP-1 mRNA induction was much weaker and occurred only after a pronounced rise in MCP-1 protein. Thus, MCP-1 in draining LNs was primarily derived from inflamed skin. In MCP-1−/− mice, intracutaneously injected MCP-1 accumulated rapidly in the draining LNs where it enhanced monocyte recruitment. Intravital microscopy showed that skin-derived MCP-1 was transported via the lymph to the luminal surface of HEVs where it triggered integrin-dependent arrest of rolling monocytes. These findings demonstrate that inflamed peripheral tissues project their local chemokine profile to HEVs in draining LNs and thereby exert “remote control” over the composition of leukocyte populations that home to these organs from the blood.
PMCID: PMC2195988  PMID: 11696600
homing; MCP-1; high endothelial venules; phagocytes; lymphatic system
10.  Induction and Suppression of an Autoimmune Disease by Oligomerized T Cell Epitopes 
T cell epitope peptides derived from proteolipid protein (PLP139–151) or myelin basic protein (MBP86–100) induce experimental autoimmune encephalomyelitis (EAE) in “susceptible” strains of mice (e.g., SJL/J). In this study, we show that the encephalitogenic effect of these epitopes when injected subcutaneously in complete Freund's adjuvant was significantly enhanced if administered to the animal in a multimerized form as a T cell epitope oligomer (i.e., as multiple repeats of the peptide epitope, such as 16-mers). Oligomer-treated SJL/J mice developed EAE faster and showed a more severe progression of the disease than animals treated with peptide alone. In addition, haplotype-matched B10.S mice, “resistant” to EAE induction by peptide, on injection of 16-mers developed a severe form of EAE. Even more striking, however, was the dramatic suppression of incidence and severity of the disease, seen after single intravenous injections of only 50 μg of the PLP139–151 16-mer, administered to SJL/J mice 7 d after the induction of the disease. Although relapse occurred at about day 45, an additional injection several days before that maintained the suppression. Importantly, the specific suppressive effect of oligomer treatment was also evident if EAE was induced with spinal cord homogenate instead of the single peptide antigen. By contrast, the PLP139–151 peptide accelerated rather than retarded the progression of disease.
PMCID: PMC2195838  PMID: 10684863
apoptosis; anergy; high zone tolerance; experimental autoimmune encephalomyelitis; multimer
11.  The Cc Chemokine Thymus-Derived Chemotactic Agent 4 (Tca-4, Secondary Lymphoid Tissue Chemokine, 6ckine, Exodus-2) Triggers Lymphocyte Function–Associated Antigen 1–Mediated Arrest of Rolling T Lymphocytes in Peripheral Lymph Node High Endothelial Venules 
T cell homing to peripheral lymph nodes (PLNs) is defined by a multistep sequence of interactions between lymphocytes and endothelial cells in high endothelial venules (HEVs). After initial tethering and rolling via L-selectin, firm adhesion of T cells requires rapid upregulation of lymphocyte function–associated antigen 1 (LFA-1) adhesiveness by a previously unknown pathway that activates a Gαi-linked receptor. Here, we used intravital microscopy of murine PLNs to study the role of thymus-derived chemotactic agent (TCA)-4 (secondary lymphoid tissue chemokine, 6Ckine, Exodus-2) in homing of adoptively transferred T cells from T-GFP mice, a transgenic strain that expresses green fluorescent protein (GFP) selectively in naive T lymphocytes (TGFP cells). TCA-4 was constitutively presented on the luminal surface of HEVs, where it was required for LFA-1 activation on rolling TGFP cells. Desensitization of the TCA-4 receptor, CC chemokine receptor 7 (CCR7), blocked TGFP cell adherence in wild-type HEVs, whereas desensitization to stromal cell–derived factor (SDF)-1α (the ligand for CXC chemokine receptor 4 [CXCR4]) did not affect TGFP cell behavior. TCA-4 protein was not detected on the luminal surface of PLN HEVs in plt/plt mice, which have a congenital defect in T cell homing to PLNs. Accordingly, TGFP cells rolled but did not arrest in plt/plt HEVs. When TCA-4 was injected intracutaneously into plt/plt mice, the chemokine entered afferent lymph vessels and accumulated in draining PLNs. 2 h after intracutaneous injection, luminal presentation of TCA-4 was detectable in a subset of HEVs, and LFA-1–mediated TGFP cell adhesion was restored in these vessels. We conclude that TCA-4 is both required and sufficient for LFA-1 activation on rolling T cells in PLN HEVs. This study also highlights a hitherto undocumented role for chemokines contained in afferent lymph, which may modulate leukocyte recruitment in draining PLNs.
PMCID: PMC2195804  PMID: 10620605
homing; intravital microscopy; adhesion; T cell
12.  The Coordinated Action of CC Chemokines in the Lung Orchestrates Allergic Inflammation and Airway Hyperresponsiveness  
The complex pathophysiology of lung allergic inflammation and bronchial hyperresponsiveness (BHR) that characterize asthma is achieved by the regulated accumulation and activation of different leukocyte subsets in the lung. The development and maintenance of these processes correlate with the coordinated production of chemokines. Here, we have assessed the role that different chemokines play in lung allergic inflammation and BHR by blocking their activities in vivo. Our results show that blockage of each one of these chemokines reduces both lung leukocyte infiltration and BHR in a substantially different way. Thus, eotaxin neutralization reduces specifically BHR and lung eosinophilia transiently after each antigen exposure. Monocyte chemoattractant protein (MCP)-5 neutralization abolishes BHR not by affecting the accumulation of inflammatory leukocytes in the airways, but rather by altering the trafficking of the eosinophils and other leukocytes through the lung interstitium. Neutralization of RANTES (regulated upon activation, normal T cell expressed and secreted) receptor(s) with a receptor antagonist decreases significantly lymphocyte and eosinophil infiltration as well as mRNA expression of eotaxin and RANTES. In contrast, neutralization of one of the ligands for RANTES receptors, macrophage-inflammatory protein 1α, reduces only slightly lung eosinophilia and BHR. Finally, MCP-1 neutralization diminishes drastically BHR and inflammation, and this correlates with a pronounced decrease in monocyte- and lymphocyte-derived inflammatory mediators. These results suggest that different chemokines activate different cellular and molecular pathways that in a coordinated fashion contribute to the complex pathophysiology of asthma, and that their individual blockage results in intervention at different levels of these processes.
PMCID: PMC2525544  PMID: 9653092
chemokines; allergic inflammation; bronchial hyperresponsiveness; eosinophilia; leukocytes
13.  The Orphan Seven-Transmembrane Receptor Apj Supports the Entry of Primary T-Cell-Line-Tropic and Dualtropic Human Immunodeficiency Virus Type 1 
Journal of Virology  1998;72(7):6113-6118.
Human immunodeficiency virus type 1 (HIV-1) enters target cells by sequential binding to CD4 and specific seven-transmembrane-segment (7TMS) coreceptors. Viruses use the chemokine receptor CCR5 as a coreceptor in the early, asymptomatic stages of HIV-1 infection but can adapt to the use of other receptors such as CXCR4 and CCR3 as the infection proceeds. Here we identify one such coreceptor, Apj, which supported the efficient entry of several primary T-cell-line tropic (T-tropic) and dualtropic HIV-1 isolates and the simian immunodeficiency virus SIVmac316. Another 7TMS protein, CCR9, supported the less efficient entry of one primary T-tropic isolate. mRNAs for both receptors were present in phytohemagglutinin- and interleukin-2-activated peripheral blood mononuclear cells. Apj and CCR9 share with other coreceptors for HIV-1 and SIV an N-terminal region rich in aromatic and acidic residues. These results highlight properties common to 7TMS proteins that can function as HIV-1 coreceptors, and they may contribute to an understanding of viral evolution in infected individuals.
PMCID: PMC110417  PMID: 9621075
14.  Use of Murine CXCR-4 as a Second Receptor by Some T-Cell-Tropic Human Immunodeficiency Viruses 
Journal of Virology  1998;72(2):1652-1656.
The human CXCR-4 molecule serves as a second receptor for primary, T-cell-tropic, and laboratory-adapted human immunodeficiency virus type 1 (HIV-1) isolates. Here we show that murine CXCR-4 can support the entry of some of these HIV-1 isolates. Differences between mouse and human CXCR-4 in the ability to function as an HIV-1 receptor are determined by sequences in the second extracellular loop of the CXCR-4 protein.
PMCID: PMC124650  PMID: 9445072
15.  RANTES and Monocyte Chemoattractant Protein–1 (MCP-1) Play an Important Role in the Inflammatory Phase of Crescentic Nephritis, but Only MCP-1 Is Involved in Crescent Formation and Interstitial Fibrosis 
The Journal of Experimental Medicine  1997;185(7):1371-1380.
The involvement of chemokines in inflammation is well established, but their functional role in disease progression, and particularly in the development of fibrosis, is not yet understood. To investigate the functional role that the chemokines monocyte chemoattractant protein–1 (MCP-1) and RANTES play in inflammation and the progression to fibrosis during crescentic nephritis we have developed and characterized a murine model for this syndrome. Significant increases in T-lymphocytes and macrophages were observed within glomeruli and interstitium, paralleled by an induction of mRNA expression of MCP-1 and RANTES, early after disease initiation. Blocking the function of MCP-1 or RANTES resulted in significant decreases in proteinuria as well as in numbers of infiltrating leukocytes, indicating that both MCP-1 and RANTES (regulated upon activation in normal T cells expressed and secreted) play an important role in the inflammatory phase of crescentic nephritis. In addition, neutralization of MCP-1 resulted in a dramatic decrease in both glomerular crescent formation and deposition of type I collagen. These results highlight a novel role for MCP-1 in crescent formation and development of interstitial fibrosis, and indicate that in addition to recruiting inflammatory cells this chemokine is critically involved in irreversible tissue damage.
PMCID: PMC2196251  PMID: 9104823
16.  IMMUNE RESPONSES IN VITRO  
The effects of alloantisera against leukocyte alloantigens on plaque-forming cell (PFC) responses to sheep erythrocytes and the terpolymer of L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) by mouse spleen cells in vitro have been investigated. Polyspecific antibodies against both H-2 and non-H-2 alloantigens on responding spleen cells suppressed both IgM and IgG PFC responses; antisera against alloantigens coded for by the K and I regions, but not the D region, of the H-2 complex also effectively suppressed PFC responses. The suppression was not due to cytotoxicity to the spleen cells or anti-immunoglobulin activity in the sera and was directly related to the amount of antiserum added to the cultures. The suppression was specific for spleen cells against which the alloantiserum was directed. The alloantisera suppressed responses most effectively when present during the first 24 h of incubation, and although not rendering lymphoid cells incapable of developing PFC responses after removal of noncell-bound antibody, did act by interfering with successful initiation of the PFC response. The alloantisera suppressed both IgM and IgG PFC responses when directed against alloantigens only on macrophages, but selectively suppressed IgG responses when directed against alloantigens only on lymphoid cells. The alloantisera did not interfere with the ability of macrophages to bind GAT or to support the viability of the lymphoid cells, but did interfere with the ability of macrophage-associated antigen to effectively stimulate antibody responses by the lymphoid cells. Possible mechanisms for the effects of alloantisera on macrophages and the selective suppression of IgG responses when the antisera are directed against alloantigens on lymphoid cells are discussed with reference to our current understanding of genetic restrictions governing cell interactions in the development of antibody responses in mice.
PMCID: PMC2139626  PMID: 4610076
17.  CHARACTERIZATION OF A NEW INTRA-H-2 RECOMBINANT  
This report characterizes the intra-H-2 crossover in the D2.GD mouse strain. Recombination occurred within the I region between the immune response (Ir) gene controlling immune responsiveness to ragweed extract (RE). Ir-RE, and the Ir gene governing responsiveness to the random linear terpolymers of glutamic acid and lysine with either tyrosine or pheylalanine (Ir-GLT and Ir-GLφ). The Ir-RE gene was tentatively located in the Ir-1A subregion and the Ir-GLT and Ir-GLφ gene(s) tentatively placed in the Ir-1B subregion. The importance of this recombinant strain to further studies on the fine structure of the I region is discussed.
PMCID: PMC2139613  PMID: 4412395
18.  CELL INTERACTIONS BETWEEN HISTOINCOMPATIBLE T AND B LYMPHOCYTES  
In our initial studies on the question of histocompatibility requirements in T-B-cell interactions, we found that no cooperation occurred with mixtures of T and B cells from BALB/c (H-2d) and A/J (H-2a) donors, respectively (1). These particular strains are identical for genes in the S and D regions of the H-2 complex but possess major differences at the K-end. Many differences are known to exist in the I region as well. Thus, these early data indicated that gene identities only at the D-end are insufficient to permit optimal cooperative interactions to occur under these conditions.
PMCID: PMC2139692  PMID: 4545898
19.  CELL INTERACTIONS BETWEEN HISTOINCOMPATIBLE T AND B LYMPHOCYTES  
In the present study we have asked the question of whether F1 carrier-primed T cells can serve as helper cells for either or both parental B cells when (a) the carrier molecule employed is under genetic control such that one parental strain is a responder and the other is a nonresponder, and (b) the determinant specificity of the parental B cells being assessed is not under genetic control and bears no relationship to the specificity of the carrier molecule. Utilizing the system of immune response gene control of responses to the terpolymer L-glutamic acid-L-lysine-L-tyrosine (GLT) to which A strain mice (H-2a) are nonresponders, whereas BALB/c (H-2d) and (BALB/c x A)F1 hybrids (CAF1) are responders, these studies demonstrate that GLT-primed T cells of CAF1 donors can provide for responder BALB/c, but not for nonresponder A/J, the required stimulus for the anti-DNP responses of DNP-specific B cells of these respective parental strains to the DNP conjugate of GLT. The implications of these findings for Ir gene function in physiologic T-B cell interactions are discussed in detail.
PMCID: PMC2139417  PMID: 4542255

Results 1-19 (19)