[Show abstract][Hide abstract] ABSTRACT: Human cytolytic T lymphocytes and natural killer cells can limit tumor growth and are being increasingly harnessed for tumor immunotherapy. One way cytolytic lymphocytes recognize tumor cells is by engagement of their activating receptor, NKG2D, by stress antigens of the MICA/B and ULBP families. This study shows that surface up-regulation of NKG2D ligands by human epithelial cells in response to ultraviolet irradiation, osmotic shock, oxidative stress, and growth factor provision is attributable to activation of the epidermal growth factor receptor (EGFR). EGFR activation causes intracellular relocalization of AUF1 proteins that ordinarily destabilize NKG2D ligand mRNAs by targeting an AU-rich element conserved within the 3' ends of most human, but not murine, NKG2D ligand genes. Consistent with these findings, NKG2D ligand expression by primary human carcinomas positively correlated with EGFR expression, which is commonly hyperactivated in such tumors, and was reduced by clinical EGFR inhibitors. Therefore, stress-induced activation of EGFR not only regulates cell growth but also concomitantly regulates the cells' immunological visibility. Thus, therapeutics designed to limit cancer cell growth should also be considered in terms of their impact on immunosurveillance.
Science translational medicine 04/2014; 6(231):231ra49. DOI:10.1126/scitranslmed.3007579 · 15.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this issue of Immunity, a study by Luoma et al. (2013) provides structural evidence for direct interactions of human Vδ1(+) T cell receptors with CD1d, capping a long trail of evidence that CD1 might be a major influence on γδ T cell biology.
[Show abstract][Hide abstract] ABSTRACT: γδ T cells are a unique and conserved population of lymphocytes that have been the subject of a recent explosion of interest owing to their essential contributions to many types of immune response and immunopathology. But what does the integration of recent and long-established studies really tell us about these cells and their place in immunology? The time is ripe to consider the evidence for their unique and crucial functions. We conclude that whereas B cells and αβ T cells are commonly thought to contribute primarily to the antigen-specific effector and memory phases of immunity, γδ T cells are distinct in that they combine conventional adaptive features (inherent in their T cell receptors and pleiotropic effector functions) with rapid, innate-like responses that can place them in the initiation phase of immune reactions. This underpins a revised perspective on lymphocyte biology and the regulation of immunogenicity.
[Show abstract][Hide abstract] ABSTRACT: DNA damage or other physicochemical stresses may increase the expression of major histocompatibility complex class I-related stress antigens, which then activate lymphocytes. This lymphoid stress surveillance (LSS) not only can limit tumor formation but may also promote immunopathology. MICA is a highly polymorphic human stress antigen implicated in tumor surveillance, inflammation, and transplant rejection. However, LSS has not been conclusively demonstrated in humans, and the functional role for MICA polymorphisms remains to be established. We show that MICA coding sequence polymorphisms substantially affected RNA and protein expression. All donors tested showed LSS responses of γδ T and natural killer cells, but unexpectedly, each was individually "tuned." Hence, some responded optimally to highly expressed alleles, whereas others responded better to lower MICA expression, challenging the orthodoxy that higher stress antigen levels promote greater responsiveness. These individual variations in LSS tuning may help explain patient-specific differences in tumor immune surveillance, transplant rejection, and inflammation, as well as provide insight into immune evasion and immunosuppression.
Science translational medicine 11/2011; 3(113):113ra124. DOI:10.1126/scitranslmed.3002922 · 15.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surface ATP synthase (namely ecto-F₁-ATPase) expression is related to different biological effects, such as regulation of HDL uptake by hepatocytes, endothelial cell proliferation or antitumor activity of Vγ9/Vδ2 T lymphocytes. This paper reviews the recently discovered functions and regulations of ecto-F₁-ATPase. Particularly, the role of the F₁-ATPase pathway(s) in HDL-cholesterol uptake and apoA-I-mediated endothelial protection suggests its potential importance in reverse cholesterol transport and its regulation might represent a potential therapeutic target for HDL-related therapy for cardiovascular diseases. Therefore, it is timely for us to better understand how this ecto-enzyme and downstream pathways are regulated and to develop pharmacologic interventions.
World Journal of Gastroenterology 12/2010; 16(47):5925-35. DOI:10.3748/wjg.v16.i47.5925 · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study we demonstrate a new form of immunoregulation: engagement on CD4(+) T cells of the complement regulator CD46 promoted the effector potential of T helper type 1 cells (T(H)1 cells), but as interleukin 2 (IL-2) accumulated, it switched cells toward a regulatory phenotype, attenuating IL-2 production via the transcriptional regulator ICER/CREM and upregulating IL-10 after interaction of the CD46 tail with the serine-threonine kinase SPAK. Activated CD4(+) T cells produced CD46 ligands, and blocking CD46 inhibited IL-10 production. Furthermore, CD4(+) T cells in rheumatoid arthritis failed to switch, consequently producing excessive interferon-gamma (IFN-gamma). Finally, gammadelta T cells, which rarely produce IL-10, expressed an alternative CD46 isoform and were unable to switch. Nonetheless, coengagement of T cell antigen receptor (TCR) gammadelta and CD46 suppressed effector cytokine production, establishing that CD46 uses distinct mechanisms to regulate different T cell subsets during an immune response.
[Show abstract][Hide abstract] ABSTRACT: Human Vgamma9Vdelta2 T lymphocytes are activated by phosphoantigens provided exogenously or produced by tumors and infected cells. Activation requires a contact between Vgamma9Vdelta2 cells and neighboring cells. We previously reported a role for cell surface F1-adenosine triphosphatase (ATPase) in T cell activation by tumors and specific interactions between Vgamma9Vdelta2 TCRs and purified F1-ATPase. 721.221 cells do not express surface F1-ATPase and do not support phosphoantigen responses unless they are rendered apoptotic by high doses of zoledronate, a treatment that promotes F1-expression as well as endogenous phosphoantigen production. By monitoring calcium flux in single cells, we show in this study that contact of T cells with F1-ATPase on polystyrene beads can partially replace the cell-cell contact stimulus during phosphoantigen responses. Triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester, an adenylated derivative of isopentenyl pyrophosphate, can stably bind to F1-ATPase-coated beads and promotes TCR aggregation, lymphokine secretion, and activation of the cytolytic process provided that nucleotide pyrophosphatase activity is present. It also acts as an allosteric activator of F1-ATPase. In the absence of Vgamma9Vdelta2 cells, triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester immobilized on F1-ATPase is protected from nucleotide pyrophosphatase activity, as is the antigenic activity of stimulatory target cells. Our experiments support the notion that Vgamma9Vdelta2 T cells are dedicated to the recognition of phosphoantigens on cell membranes in the form of nucleotide derivatives that can bind to F1-ATPase acting as a presentation molecule.
The Journal of Immunology 06/2010; 184(12):6920-8. DOI:10.4049/jimmunol.0904024 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human Vgamma9Vdelta2 T lymphocytes recognize phosphorylated alkyl Ags. Isopentenyl pyrophosphate (IPP) was previously proposed as the main Ag responsible for Vgamma9Vdelta2 T cell activation by cancer cells. However, triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester (ApppI), a metabolite in which the isopentenyl moiety is linked to ATP, was reported in cells activated with aminobisphosphonates. The contribution of this compound to tumor-stimulatory activity was thus examined. ApppI induces selective expansion of Vgamma9Vdelta2 T cells from PBMCs. In the absence of APCs, however, ApppI has little stimulatory activity on Vgamma9Vdelta2 T cells, and optimal activation with ApppI requires addition of a nucleotide pyrophosphatase releasing IPP plus AMP. Thus, ApppI has no intrinsic stimulatory activity. Nevertheless, stimulation by ApppI is strengthened by the presence of APCs. Moreover, in contrast to IPP, ApppI can be efficiently pulsed on dendritic cells as well as on nonprofessional APCs. Pulsed APCs display stable and phosphatase-resistant stimulatory activity, indicative of Ag modification. HPLC analysis of tumor cell extracts indicates that latent phosphoantigenic activity is stored intracellularly in the Vgamma9Vdelta2 cell-sensitive tumor Daudi and can be activated by a nucleotide pyrophosphatase activity. The presence of ApppI in Daudi cell extracts was demonstrated by mass spectrometry. Nucleotidic Ags such as ApppI are thus a storage form of phosphoantigen which may represent a major source of phosphoantigenic activity in tumor cells. The unique properties of ApppI may be important for the design of Ags used in anticancer immunotherapeutic protocols using Vgamma9Vdelta2 cells.
The Journal of Immunology 09/2009; 183(6):3848-57. DOI:10.4049/jimmunol.0901085 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Subunits of the mitochondrial ATP synthase complex are expressed on the surface of tumors, bind the TCR of human Vγ9/Vδ2 lymphocytes and promote their cytotoxicity. Present experiments show that detection of the complex (called ecto-F1-ATPase) at the cell surface by immunofluorescence correlates with low MHC-class I antigen expression. Strikingly, the α and β chains of ecto-F1-ATPase are detected in membrane protein precipitates from immunofluorescence-negative cells, suggesting that ATPase epitopes are masked. Removal of β2-microglobulin by mild acid treatment so that most surface MHC-I molecules become free heavy chains reveals F1-ATPase epitopes on MHC-I+ cell lines. Ecto- F1-ATPase is detected by immunofluorescence on primary fibroblasts which express moderate levels of MHC-I antigens. Upregulation of MHC-I on these cells following IFN-γ and/or TNF-α treatment induces a dose-dependent disappearance of F1-ATPase epitopes. Finally, biotinylated F1-ATPase cell surface components co-immunoprecipitate with MHC-I molecules confirming the association of both complexes on Raji cells. Confocal microscopy analysis of MHC-I and ecto-F1-ATPase β chain expression on HepG2 cells shows a colocalization of both complexes in punctate membrane domains. This demonstrates that the TCR target F1-ATPase is in close contact with MHC-I antigens which are known to control Vγ9/Vδ2 T cell activity through binding to natural killer inhibitory receptors.
[Show abstract][Hide abstract] ABSTRACT: We have previously demonstrated on human hepatocytes that apolipoprotein A-I binding to an ecto-F(1)-ATPase stimulates the production of extracellular ADP that activates a P2Y(13)-mediated high-density lipoprotein (HDL) endocytosis pathway. Therefore, we investigated the mechanisms controlling the extracellular ATP/ADP level in hepatic cell lines and primary cultures to determine their impact on HDL endocytosis. Here we show that addition of ADP to the cell culture medium induced extracellular ATP production that was due to adenylate kinase [see text] and nucleoside diphosphokinase [see text] activities, but not to ATP synthase activity. We further observed that in vitro modulation of both ecto-NDPK and AK activities could regulate the ADP-dependent HDL endocytosis. But interestingly, only AK appeared to naturally participate in the pathway by consuming the ADP generated by the ecto-F(1)-ATPase. Thus controlling the extracellular ADP level is a potential target for reverse cholesterol transport regulation.
Cellular and Molecular Life Sciences CMLS 01/2007; 63(23):2829-37. DOI:10.1007/s00018-006-6325-y · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent findings reveal unanticipated connections between the fields of lipid metabolism and immunology. They concern gammadelta and NKT cells, nonconventional T cell populations that do not recognize protein antigens and are involved in immunity against cancer, defense against infections, or in regulation of classical immune responses. In this review, we summarize data linking perturbations of apolipoprotein levels and nonconventional T cells with inflammatory processes such as autoimmune diseases or atherosclerosis. We integrate and discuss recent findings on the implication of apolipoproteins in antigen recognition by gammadelta and NKT cells, with emphasis on apolipoproteins A-I and E. These findings also provide indications that apolipoproteins influence antitumor immunosurveillance.
Immunologic Research 02/2005; 33(3):241-55. · 3.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent findings reveal unanticipated connections between the fields of lipid metabolism and immunology. They concern ψδ and
NKT cells, nonconventional T cell populations that do not recognize protein antigens and are involved in immunity against
cancer, defense against infections, or in regulation of classical immune responses. In this review, we summarize data linking
perturbations of apolipoprotein levels and nonconventional T cells with inflammatory processes such as autoimmune diseases
or atherosclerosis. We integrate and discuss recent findings on the implication of apolipoproteins in antigen recognition
by ψδ and NKT cells, with emphasis on apolipoproteins A-I and E. These findings also provide indications that apolipoproteins
influence antitumor immunosurveillance.
Immunologic Research 01/2005; 33(3):241-255. DOI:10.1385/IR:33:3:241 · 3.10 Impact Factor