Role of Polyamines in Immune Cell Functions
Rebecca S Hesterberg, John L Cleveland, Pearlie K Epling-Burnette, Rebecca S Hesterberg, John L Cleveland, Pearlie K Epling-Burnette
Abstract
The immune system is remarkably responsive to a myriad of invading microorganisms and provides continuous surveillance against tissue damage and developing tumor cells. To achieve these diverse functions, multiple soluble and cellular components must react in an orchestrated cascade of events to control the specificity, magnitude and persistence of the immune response. Numerous catabolic and anabolic processes are involved in this process, and prominent roles for l-arginine and l-glutamine catabolism have been described, as these amino acids serve as precursors of nitric oxide, creatine, agmatine, tricarboxylic acid cycle intermediates, nucleotides and other amino acids, as well as for ornithine, which is used to synthesize putrescine and the polyamines spermidine and spermine. Polyamines have several purported roles and high levels of polyamines are manifest in tumor cells as well in autoreactive B- and T-cells in autoimmune diseases. In the tumor microenvironment, l-arginine catabolism by both tumor cells and suppressive myeloid cells is known to dampen cytotoxic T-cell functions suggesting there might be links between polyamines and T-cell suppression. Here, we review studies suggesting roles of polyamines in normal immune cell function and highlight their connections to autoimmunity and anti-tumor immune cell function.
Keywords: B-lymphocytes; T-lymphocytes; autoimmunity; epigenetics; immunity; metabolism; tumor immunity.
Conflict of interest statement
The authors receive support from Celgene Corporation through a grant to the Moffitt Cancer Center & Research Institute. The content of this manuscript is not influenced by this association.
Figures
References
- Green D.R. Metabolism and immunity: The old and the new. Semin. Immunol. 2012;24:383. doi: 10.1016/j.smim.2013.02.001.
- Halligan D.N., Murphy S.J., Taylor C.T. The hypoxia-inducible factor (HIF) couples immunity with metabolism. Semin. Immunol. 2016;28:469–477. doi: 10.1016/j.smim.2016.09.004.
- Scharping N.E., Delgoffe G.M. Tumor Microenvironment Metabolism: A New Checkpoint for Anti-Tumor Immunity. Vaccines (Basel) 2016;4:46. doi: 10.3390/vaccines4040046.
- Pearce E.L., Pearce E.J. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013;38:633–643. doi: 10.1016/j.immuni.2013.04.005.
- Michalek R.D., Rathmell J.C. The metabolic life and times of a T-cell. Immunol. Rev. 2010;236:190–202. doi: 10.1111/j.1600-065X.2010.00911.x.
- Gerriets V.A., Rathmell J.C. Metabolic pathways in T cell fate and function. Trends Immunol. 2012;33:168–173. doi: 10.1016/j.it.2012.01.010.
- Olenchock B.A., Rathmell J.C., Vander Heiden M.G. Biochemical Underpinnings of Immune Cell Metab.olic Phenotypes. Immunity. 2017;46:703–713. doi: 10.1016/j.immuni.2017.04.013.
- O‘Neill L.A., Kishton R.J., Rathmell J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 2016;16:553–565. doi: 10.1038/nri.2016.70.
- Goodnow C.C., Sprent J., Fazekas de St Groth B., Vinuesa C.G. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature. 2005;435:590–597. doi: 10.1038/nature03724.
- Flajnik M.F., Kasahara M. Origin and evolution of the adaptive immune system: Genetic events and selective pressures. Nat. Rev. Genet. 2010;11:47–59. doi: 10.1038/nrg2703.
- Kondo M., Weissman I.L., Akashi K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell. 1997;91:661–672. doi: 10.1016/S0092-8674(00)80453-5.
- Akashi K., Traver D., Kondo M., Weissman I.L. Lymphoid development from hematopoietic stem cells. Int. J. Hematol. 1999;69:217–226.
- Akashi K., Traver D., Miyamoto T., Weissman I.L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature. 2000;404:193–197. doi: 10.1038/35004599.
- Morrison S.J., Hemmati H.D., Wandycz A.M., Weissman I.L. The purification and characterization of fetal liver hematopoietic stem cells. Proc. Natl. Acad. Sci. USA. 1995;92:10302–10306. doi: 10.1073/pnas.92.22.10302.
- Venkitaraman A.R., Williams G.T., Dariavach P., Neuberger M.S. The B-cell antigen receptor of the five immunoglobulin classes. Nature. 1991;352:777–781. doi: 10.1038/352777a0.
- Pape K.A., Catron D.M., Itano A.A., Jenkins M.K. The humoral immune response is initiated in lymph nodes by B cells that acquire soluble antigen directly in the follicles. Immunity. 2007;26:491–502. doi: 10.1016/j.immuni.2007.02.011.
- Tonegawa S. Somatic generation of antibody diversity. Nature. 1983;302:575–581. doi: 10.1038/302575a0.
- Garside P., Ingulli E., Merica R.R., Johnson J.G., Noelle R.J., Jenkins M.K. Visualization of specific B and T lymphocyte interactions in the lymph node. Science. 1998;281:96–99. doi: 10.1126/science.281.5373.96.
- McAdam A.J., Greenwald R.J., Levin M.A., Chernova T., Malenkovich N., Ling V., Freeman G.J., Sharpe A.H. ICOS is critical for CD40-mediated antibody class switching. Nature. 2001;409:102–105. doi: 10.1038/35051107.
- Honjo T., Kinoshita K., Muramatsu M. Molecular mechanism of class switch recombination: Linkage with somatic hypermutation. Annu. Rev. Immunol. 2002;20:165–196. doi: 10.1146/annurev.immunol.20.090501.112049.
- Gong S., Nussenzweig M.C. Regulation of an early developmental checkpoint in the B cell pathway by Ig β. Science. 1996;272:411–414. doi: 10.1126/science.272.5260.411.
- Caro-Maldonado A., Wang R., Nichols A.G., Kuraoka M., Milasta S., Sun L.D., Gavin A.L., Abel E.D., Kelsoe G., Green D.R., et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J. Immunol. 2014;192:3626–3636. doi: 10.4049/jimmunol.1302062.
- Jones R.G., Pearce E.J. MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells. Immunity. 2017;46:730–742. doi: 10.1016/j.immuni.2017.04.028.
- Siska P.J., van der Windt G.J., Kishton R.J., Cohen S., Eisner W., MacIver N.J., Kater A.P., Weinberg J.B., Rathmell J.C. Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia. J. Immunol. 2016;197:2532–2540. doi: 10.4049/jimmunol.1502464.
- Nilsson J.A., Keller U.B., Baudino T.A., Yang C., Norton S., Old J.A., Nilsson L.M., Neale G., Kramer D.L., Porter C.W., et al. Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation. Cancer Cell. 2005;7:433–444. doi: 10.1016/j.ccr.2005.03.036.
- Bello-Fernandez C., Packham G., Cleveland J.L. The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc. Natl. Acad. Sci. USA. 1993;90:7804–7808. doi: 10.1073/pnas.90.16.7804.
- Tessem M.B., Bertilsson H., Angelsen A., Bathen T.F., Drablos F., Rye M.B. A Balanced Tissue Composition Reveals New Metabolic and Gene Expression Markers in Prostate Cancer. PLoS ONE. 2016;11:e0153727. doi: 10.1371/journal.pone.0153727.
- Pegg A.E. Regulation of ornithine decarboxylase. J. Biol. Chem. 2006;281:14529–14532. doi: 10.1074/jbc.R500031200.
- Pendeville H., Carpino N., Marine J.C., Takahashi Y., Muller M., Martial J.A., Cleveland J.L. The ornithine decarboxylase gene is essential for cell survival during early murine development. Mol. Cell. Biol. 2001;21:6549–6558. doi: 10.1128/MCB.21.19.6549-6558.2001.
- Nitta T., Igarashi K., Yamashita A., Yamamoto M., Yamamoto N. Involvement of polyamines in B cell receptor-mediated apoptosis: Spermine functions as a negative modulator. Exp. Cell Res. 2001;265:174–183. doi: 10.1006/excr.2001.5177.
- Ohmori H., Egusa H., Ueura N., Matsumoto Y., Kanayama N., Hikida M. Selective augmenting effects of nitric oxide on antigen-specific IgE response in mice. Immunopharmacology. 2000;46:55–63. doi: 10.1016/S0162-3109(99)00158-7.
- Kramer D.L., Diegelman P., Jell J., Vujcic S., Merali S., Porter C.W. Polyamine acetylation modulates polyamine metabolic flux, a prelude to broader metabolic consequences. J. Biol. Chem. 2008;283:4241–4251. doi: 10.1074/jbc.M706806200.
- Akamatsu Y., Monroe R., Dudley D.D., Elkin S.K., Gartner F., Talukder S.R., Takahama Y., Alt F.W., Bassing C.H., Oettinger M.A. Deletion of the RAG2 C terminus leads to impaired lymphoid development in mice. Proc. Natl. Acad. Sci. USA. 2003;100:1209–1214. doi: 10.1073/pnas.0237043100.
- Mombaerts P., Iacomini J., Johnson R.S., Herrup K., Tonegawa S., Papaioannou V.E. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992;68:869–877. doi: 10.1016/0092-8674(92)90030-G.
- Zhu C., Roth D.B. Characterization of coding ends in thymocytes of scid mice: Implications for the mechanism of V(D)J recombination. Immunity. 1995;2:101–112. doi: 10.1016/1074-7613(95)90082-9.
- Zlotoff D.A., Sambandam A., Logan T.D., Bell J.J., Schwarz B.A., Bhandoola A. CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus. Blood. 2010;115:1897–1905. doi: 10.1182/blood-2009-08-237784.
- Zlotoff D.A., Zhang S.L., De Obaldia M.E., Hess P.R., Todd S.P., Logan T.D., Bhandoola A. Delivery of progenitors to the thymus limits T-lineage reconstitution after bone marrow transplantation. Blood. 2011;118:1962–1970. doi: 10.1182/blood-2010-12-324954.
- Meredith M., Zemmour D., Mathis D., Benoist C. Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat. Immunol. 2015;16:942–949. doi: 10.1038/ni.3247.
- Wolfer A., Wilson A., Nemir M., MacDonald H.R., Radtke F. Inactivation of Notch1 impairs VDJβ rearrangement and allows pre-TCR-independent survival of early αβ Lineage Thymocytes. Immunity. 2002;16:869–879. doi: 10.1016/S1074-7613(02)00330-8.
- Tanigaki K., Tsuji M., Yamamoto N., Han H., Tsukada J., Inoue H., Kubo M., Honjo T. Regulation of αβ/γδ T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling. Immunity. 2004;20:611–622. doi: 10.1016/S1074-7613(04)00109-8.
- Mombaerts P., Clarke A.R., Rudnicki M.A., Iacomini J., Itohara S., Lafaille J.J., Wang L., Ichikawa Y., Jaenisch R., Hooper M.L., et al. Mutations in T-cell antigen receptor genes α and β block thymocyte development at different stages. Nature. 1992;360:225–231. doi: 10.1038/360225a0.
- Haas W., Pereira P., Tonegawa S. Gamma/delta cells. Annu. Rev. Immunol. 1993;11:637–685. doi: 10.1146/annurev.iy.11.040193.003225.
- Germain R.N. T-cell development and the CD4-CD8 lineage decision. Nat. Rev. Immunol. 2002;2:309–322. doi: 10.1038/nri798.
- Gao G.F., Tormo J., Gerth U.C., Wyer J.R., McMichael A.J., Stuart D.I., Bell J.I., Jones E.Y., Jakobsen B.K. Crystal structure of the complex between human CD8αα and HLA-A2. Nature. 1997;387:630–634. doi: 10.1038/42523.
- Josefowicz S.Z., Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity. 2009;30:616–625. doi: 10.1016/j.immuni.2009.04.009.
- Bendelac A., Savage P.B., Teyton L. The biology of NKT cells. Annu. Rev. Immunol. 2007;25:297–336. doi: 10.1146/annurev.immunol.25.022106.141711.
- McDonald B.D., Bunker J.J., Ishizuka I.E., Jabri B., Bendelac A. Elevated T cell receptor signaling identifies a thymic precursor to the TCRαβ+ CD4−CD8β− intraepithelial lymphocyte lineage. Immunity. 2014;41:219–229. doi: 10.1016/j.immuni.2014.07.008.
- Cheroutre H. IELs: Enforcing law and order in the court of the intestinal epithelium. Immunol. Rev. 2005;206:114–131. doi: 10.1111/j.0105-2896.2005.00284.x.
- Nagaraj S., Gupta K., Pisarev V., Kinarsky L., Sherman S., Kang L., Herber D.L., Schneck J., Gabrilovich D.I. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat. Med. 2007;13:828–835. doi: 10.1038/nm1609.
- Bertram E.M., Dawicki W., Watts T.H. Role of T cell costimulation in anti-viral immunity. Semin. Immunol. 2004;16:185–196. doi: 10.1016/j.smim.2004.02.006.
- Croft M. Costimulation of T cells by OX40, 4-1BB, and CD27. Cytokine Growth Factor Rev. 2003;14:265–273. doi: 10.1016/S1359-6101(03)00025-X.
- Gramaglia I., Weinberg A.D., Lemon M., Croft M. Ox-40 ligand: A potent costimulatory molecule for sustaining primary CD4 T cell responses. J. Immunol. 1998;161:6510–6517.
- Rogers P.R., Croft M. CD28, Ox-40, LFA-1, and CD4 modulation of Th1/Th2 differentiation is directly dependent on the dose of antigen. J. Immunol. 2000;164:2955–2963. doi: 10.4049/jimmunol.164.6.2955.
- Cantrell D.A. Transgenic analysis of thymocyte signal transduction. Nat. Rev. Immunol. 2002;2:20–27. doi: 10.1038/nri703.
- Derbinski J., Schulte A., Kyewski B., Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2001;2:1032–1039. doi: 10.1038/ni723.
- Abramson J., Giraud M., Benoist C., Mathis D. Aire‘s partners in the molecular control of immunological tolerance. Cell. 2010;140:123–135. doi: 10.1016/j.cell.2009.12.030.
- Danan-Gotthold M., Guyon C., Giraud M., Levanon E.Y., Abramson J. Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells. Genome Biol. 2016;17:219. doi: 10.1186/s13059-016-1079-9.
- Koh A.S., Kingston R.E., Benoist C., Mathis D. Global relevance of Aire binding to hypomethylated lysine-4 of histone-3. Proc. Natl. Acad. Sci. USA. 2010;107:13016–13021. doi: 10.1073/pnas.1004436107.
- Giraud M., Yoshida H., Abramson J., Rahl P.B., Young R.A., Mathis D., Benoist C. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. Proc. Natl. Acad. Sci. USA. 2012;109:535–540. doi: 10.1073/pnas.1119351109.
- Herzig Y., Nevo S., Bornstein C., Brezis M.R., Ben-Hur S., Shkedy A., Eisenberg-Bord M., Levi B., Delacher M., Goldfarb Y., et al. Transcriptional programs that control expression of the autoimmune regulator gene Aire. Nat. Immunol. 2017;18:161–172. doi: 10.1038/ni.3638.
- Chen L., Flies D.B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 2013;13:227–242. doi: 10.1038/nri3405.
- Ito K., Igarashi K. Polyamine regulation of the synthesis of thymidine kinase in bovine lymphocytes. Arch. Biochem. Biophys. 1990;278:277–283. doi: 10.1016/0003-9861(90)90260-6.
- Wang R., Dillon C.P., Shi L.Z., Milasta S., Carter R., Finkelstein D., McCormick L.L., Fitzgerald P., Chi H., Munger J., et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35:871–882. doi: 10.1016/j.immuni.2011.09.021.
- Hendriks J., Gravestein L.A., Tesselaar K., van Lier R.A., Schumacher T.N., Borst J. CD27 is required for generation and long-term maintenance of T cell immunity. Nat. Immunol. 2000;1:433–440. doi: 10.1038/80877.
- Agematsu K., Hokibara S., Nagumo H., Komiyama A. CD27: A memory B-cell marker. Immunol. Today. 2000;21:204–206. doi: 10.1016/S0167-5699(00)01605-4.
- Takeda K., Oshima H., Hayakawa Y., Akiba H., Atsuta M., Kobata T., Kobayashi K., Ito M., Yagita H., Okumura K. CD27-mediated activation of murine NK cells. J. Immunol. 2000;164:1741–1745. doi: 10.4049/jimmunol.164.4.1741.
- Smith A., Stanley P., Jones K., Svensson L., McDowall A., Hogg N. The role of the integrin LFA-1 in T-lymphocyte migration. Immunol. Rev. 2007;218:135–146. doi: 10.1111/j.1600-065X.2007.00537.x.
- Nocentini G., Giunchi L., Ronchetti S., Krausz L.T., Bartoli A., Moraca R., Migliorati G., Riccardi C. A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. Proc. Natl. Acad. Sci. USA. 1997;94:6216–6221. doi: 10.1073/pnas.94.12.6216.
- Khayyamian S., Hutloff A., Buchner K., Grafe M., Henn V., Kroczek R.A., Mages H.W. ICOS-ligand, expressed on human endothelial cells, costimulates Th1 and Th2 cytokine secretion by memory CD4+ T cells. Proc. Natl. Acad. Sci. USA. 2002;99:6198–6203. doi: 10.1073/pnas.092576699.
- Cai G., Freeman G.J. The CD160, BTLA, LIGHT/HVEM pathway: A bidirectional switch regulating T-cell activation. Immunol. Rev. 2009;229:244–258. doi: 10.1111/j.1600-065X.2009.00783.x.
- Tan J.T., Dudl E., LeRoy E., Murray R., Sprent J., Weinberg K.I., Surh C.D. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl. Acad. Sci. USA. 2001;98:8732–8737. doi: 10.1073/pnas.161126098.
- Wofford J.A., Wieman H.L., Jacobs S.R., Zhao Y., Rathmell J.C. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood. 2008;111:2101–2111. doi: 10.1182/blood-2007-06-096297.
- Pallard C., Stegmann A.P., van Kleffens T., Smart F., Venkitaraman A., Spits H. Distinct roles of the phosphatidylinositol 3-kinase and STAT5 pathways in IL-7-mediated development of human thymocyte precursors. Immunity. 1999;10:525–535. doi: 10.1016/S1074-7613(00)80052-7.
- Jacobs S.R., Michalek R.D., Rathmell J.C. IL-7 is essential for homeostatic control of T cell metabolism in vivo. J. Immunol. 2010;184:3461–3469. doi: 10.4049/jimmunol.0902593.
- MacIver N.J., Michalek R.D., Rathmell J.C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 2013;31:259–283. doi: 10.1146/annurev-immunol-032712-095956.
- Inoki K., Li Y., Zhu T., Wu J., Guan K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 2002;4:648–657. doi: 10.1038/ncb839.
- Inoki K., Li Y., Xu T., Guan K.L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003;17:1829–1834. doi: 10.1101/gad.1110003.
- Inoki K., Zhu T., Guan K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–590. doi: 10.1016/S0092-8674(03)00929-2.
- Iwata T.N., Ramirez J.A., Tsang M., Park H., Margineantu D.H., Hockenbery D.M., Iritani B.M. Conditional Disruption of Raptor Reveals an Essential Role for mTORC1 in B Cell Development, Survival, and Metabolism. J. Immunol. 2016;197:2250–2260. doi: 10.4049/jimmunol.1600492.
- Delgoffe G.M., Kole T.P., Zheng Y., Zarek P.E., Matthews K.L., Xiao B., Worley P.F., Kozma S.C., Powell J.D. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30:832–844. doi: 10.1016/j.immuni.2009.04.014.
- Guertin D.A., Stevens D.M., Thoreen C.C., Burds A.A., Kalaany N.Y., Moffat J., Brown M., Fitzgerald K.J., Sabatini D.M. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev. Cell. 2006;11:859–871. doi: 10.1016/j.devcel.2006.10.007.
- Shaw R.J., Kosmatka M., Bardeesy N., Hurley R.L., Witters L.A., DePinho R.A., Cantley L.C. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl. Acad. Sci. USA. 2004;101:3329–3335. doi: 10.1073/pnas.0308061100.
- Woods A., Johnstone S.R., Dickerson K., Leiper F.C., Fryer L.G., Neumann D., Schlattner U., Wallimann T., Carlson M., Carling D. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 2003;13:2004–2008. doi: 10.1016/j.cub.2003.10.031.
- Van der Windt G.J., Pearce E.L. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol. Rev. 2012;249:27–42. doi: 10.1111/j.1600-065X.2012.01150.x.
- Frauwirth K.A., Riley J.L., Harris M.H., Parry R.V., Rathmell J.C., Plas D.R., Elstrom R.L., June C.H., Thompson C.B. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002;16:769–777. doi: 10.1016/S1074-7613(02)00323-0.
- Boomer J.S., Green J.M. An enigmatic tail of CD28 signaling. Cold Spring Harb. Perspect. Biol. 2010;2:a002436. doi: 10.1101/cshperspect.a002436.
- Park S.G., Schulze-Luehrman J., Hayden M.S., Hashimoto N., Ogawa W., Kasuga M., Ghosh S. The kinase PDK1 integrates T cell antigen receptor and CD28 coreceptor signaling to induce NF-κB and activate T cells. Nat. Immunol. 2009;10:158–166. doi: 10.1038/ni.1687.
- Balagopalan L., Barr V.A., Sommers C.L., Barda-Saad M., Goyal A., Isakowitz M.S., Samelson L.E. c-Cbl-mediated regulation of LAT-nucleated signaling complexes. Mol. Cell. Biol. 2007;27:8622–8636. doi: 10.1128/MCB.00467-07.
- Verbist K.C., Guy C.S., Milasta S., Liedmann S., Kaminski M.M., Wang R., Green D.R. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature. 2016;532:389–393. doi: 10.1038/nature17442.
- Ho P.C., Bihuniak J.D., Macintyre A.N., Staron M., Liu X., Amezquita R., Tsui Y.C., Cui G., Micevic G., Perales J.C., et al. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell. 2015;162:1217–1228. doi: 10.1016/j.cell.2015.08.012.
- Maeda T., Wakasawa T., Shima Y., Tsuboi I., Aizawa S., Tamai I. Role of polyamines derived from arginine in differentiation and proliferation of human blood cells. Biol. Pharm. Bull. 2006;29:234–239. doi: 10.1248/bpb.29.234.
- Shima Y., Maeda T., Aizawa S., Tsuboi I., Kobayashi D., Kato R., Tamai I. l-arginine import via cationic amino acid transporter CAT1 is essential for both differentiation and proliferation of erythrocytes. Blood. 2006;107:1352–1356. doi: 10.1182/blood-2005-08-3166.
- Bachrach U., Persky S. Interaction of oxidized polyamines with DNA. V. Inhibition of nucleic acid synthesis. Biochim. Biophys. Acta. 1969;179:484–493. doi: 10.1016/0005-2787(69)90056-2.
- Francke B. Cell-free synthesis of herpes simplex virus DNA: The influence of polyamines. Biochemistry. 1978;17:5494–5499. doi: 10.1021/bi00618a026.
- Leveque J., Burtin F., Catros-Quemener V., Havouis R., Moulinoux J.P. The gastrointestinal polyamine source depletion enhances DFMO induced polyamine depletion in MCF-7 human breast cancer cells in vivo. Anticancer Res. 1998;18:2663–2668.
- Hessels J., Kingma A.W., Ferwerda H., Keij J., van den Berg G.A., Muskiet F.A. Microbial flora in the gastrointestinal tract abolishes cytostatic effects of α-difluoromethylornithine in vivo. Int. J. Cancer. 1989;43:1155–1164. doi: 10.1002/ijc.2910430632.
- Sugiyama S., Vassylyev D.G., Matsushima M., Kashiwagi K., Igarashi K., Morikawa K. Crystal structure of PotD, the primary receptor of the polyamine transport system in Escherichia coli. J. Biol. Chem. 1996;271:9519–9525. doi: 10.1074/jbc.271.16.9519.
- Tomitori H., Kashiwagi K., Asakawa T., Kakinuma Y., Michael A.J., Igarashi K. Multiple polyamine transport systems on the vacuolar membrane in yeast. Biochem. J. 2001;353:681–688. doi: 10.1042/bj3530681.
- Satriano J., Isome M., Casero R.A., Jr., Thomson S.C., Blantz R.C. Polyamine transport system mediates agmatine transport in mammalian cells. Am. J. Physiol. Cell Physiol. 2001;281:C329–C334. doi: 10.1152/ajpcell.2001.281.1.C329.
- Sakata K., Kashiwagi K., Igarashi K. Properties of a polyamine transporter regulated by antizyme. Biochem. J. 2000;347:297–303. doi: 10.1042/bj3470297.
- Uemura T., Stringer D.E., Blohm-Mangone K.A., Gerner E.W. Polyamine transport is mediated by both endocytic and solute carrier transport mechanisms in the gastrointestinal tract. Am. J. Physiol. Gastrointest. Liver Physiol. 2010;299:G517–G522. doi: 10.1152/ajpgi.00169.2010.
- Wolfer A., Bakker T., Wilson A., Nicolas M., Ioannidis V., Littman D.R., Lee P.P., Wilson C.B., Held W., MacDonald H.R., et al. Inactivation of Notch 1 in immature thymocytes does not perturb CD4 or CD8T cell development. Nat. Immunol. 2001;2:235–241. doi: 10.1038/85294.
- Wildin R.S., Garvin A.M., Pawar S., Lewis D.B., Abraham K.M., Forbush K.A., Ziegler S.F., Allen J.M., Perlmutter R.M. Developmental regulation of lck gene expression in T lymphocytes. J. Exp. Med. 1991;173:383–393. doi: 10.1084/jem.173.2.383.
- Dose M., Khan I., Guo Z., Kovalovsky D., Krueger A., von Boehmer H., Khazaie K., Gounari F. c-Myc mediates pre-TCR-induced proliferation but not developmental progression. Blood. 2006;108:2669–2677. doi: 10.1182/blood-2006-02-005900.
- Dezfouli S., Bakke A., Huang J., Wynshaw-Boris A., Hurlin P.J. Inflammatory disease and lymphomagenesis caused by deletion of the Myc antagonist Mnt in T cells. Mol. Cell. Biol. 2006;26:2080–2092. doi: 10.1128/MCB.26.6.2080-2092.2006.
- Jain J., Nalefski E.A., McCaffrey P.G., Johnson R.S., Spiegelman B.M., Papaioannou V., Rao A. Normal peripheral T-cell function in c-Fos-deficient mice. Mol. Cell. Biol. 1994;14:1566–1574. doi: 10.1128/MCB.14.3.1566.
- Wrighton C., Busslinger M. Direct transcriptional stimulation of the ornithine decarboxylase gene by Fos in PC12 cells but not in fibroblasts. Mol. Cell. Biol. 1993;13:4657–4669. doi: 10.1128/MCB.13.8.4657.
- Choi B.S., Martinez-Falero I.C., Corset C., Munder M., Modolell M., Muller I., Kropf P. Differential impact of l-arginine deprivation on the activation and effector functions of T cells and macrophages. J. Leukoc. Biol. 2009;85:268–277. doi: 10.1189/jlb.0508310.
- Carr E.L., Kelman A., Wu G.S., Gopaul R., Senkevitch E., Aghvanyan A., Turay A.M., Frauwirth K.A. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J. Immunol. 2010;185:1037–1044. doi: 10.4049/jimmunol.0903586.
- Hunt N.H., Fragonas J.C. Effects of anti-oxidants on ornithine decarboxylase in mitogenically-activated T lymphocytes. Biochim. Biophys. Acta. 1992;1133:261–267. doi: 10.1016/0167-4889(92)90046-E.
- Widjaja C.E., Olvera J.G., Metz P.J., Phan A.T., Savas J.N., de Bruin G., Leestemaker Y., Berkers C.R., de Jong A., Florea B.I., et al. Proteasome activity regulates CD8+ T lymphocyte metabolism and fate specification. J. Clin. Investig. 2017;127:3609–3623. doi: 10.1172/JCI90895.
- Geiger R., Rieckmann J.C., Wolf T., Basso C., Feng Y., Fuhrer T., Kogadeeva M., Picotti P., Meissner F., Mann M., et al. l-Arginine Modulates T Cell Metab.olism and Enhances Survival and Anti-tumor Activity. Cell. 2016;167:829–842. doi: 10.1016/j.cell.2016.09.031.
- Buck M.D., O‘Sullivan D., Klein Geltink R.I., Curtis J.D., Chang C.H., Sanin D.E., Qiu J., Kretz O., Braas D., van der Windt G.J., et al. Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming. Cell. 2016;166:63–76. doi: 10.1016/j.cell.2016.05.035.
- Klein Geltink R.I., O‘Sullivan D., Corrado M., Bremser A., Buck M.D., Buescher J.M., Firat E., Zhu X., Niedermann G., Caputa G., et al. Mitochondrial Priming by CD28. Cell. 2017;171:385–397. doi: 10.1016/j.cell.2017.08.018.
- Pearce E.L., Poffenberger M.C., Chang C.H., Jones R.G. Fueling immunity: Insights into metabolism and lymphocyte function. Science. 2013;342:1242454. doi: 10.1126/science.1242454.
- Alexander E.T., Minton A., Peters M.C., Phanstiel O.t., Gilmour S.K. A novel polyamine blockade therapy activates an anti-tumor immune response. Oncotarget. 2017;8:84140–84152. doi: 10.18632/oncotarget.20493.
- Mandal S., Mandal A., Johansson H.E., Orjalo A.V., Park M.H. Depletion of cellular polyamines, spermidine and spermine, causes a total arrest in translation and growth in mammalian cells. Proc. Natl. Acad. Sci. USA. 2013;110:2169–2174. doi: 10.1073/pnas.1219002110.
- Gnanaprakasam J.N., Wang R. MYC in Regulating Immunity: Metabolism and Beyond. Genes (Basel) 2017;8:88. doi: 10.3390/genes8030088.
- Ehrke M.J., Porter C.W., Eppolito C., Mihich E. Selective modulation by alpha-difluoromethylornithine of T-lymphocyte and antibody-mediated cytotoxic responses to mouse tumor allografts. Cancer Res. 1986;46:2798–2803.
- Bowlin T.L., McKown B.J., Sunkara P.S. Increased ornithine decarboxylase activity and polyamine biosynthesis are required for optimal cytolytic T lymphocyte induction. Cell. Immunol. 1987;105:110–117. doi: 10.1016/0008-8749(87)90060-8.
- Bowlin T.L., McKown B.J., Schroeder K.K. Methyl-acetylenicputrescine (MAP), an inhibitor of polyamine biosynthesis, reduces the frequency and cytolytic activity of alloantigen-induced LyT 2.2 positive lymphocytes in vivo. Int. J. Immunopharmacol. 1989;11:259–265. doi: 10.1016/0192-0561(89)90163-X.
- Bowlin T.L., Rosenberger A.L., McKown B.J. α-difluoromethylornithine, an inhibitor of polyamine biosynthesis, augments cyclosporin A inhibition of cytolytic T lymphocyte induction. Clin. Exp. Immunol. 1989;77:151–156.
- Schall R.P., Sekar J., Tandon P.M., Susskind B.M. Difluoromethylornithine (DFMO) arrests murine CTL development in the late, pre-effector stage. Immunopharmacology. 1991;21:129–143. doi: 10.1016/0162-3109(91)90016-R.
- Bowlin T.L., Davis G.F., McKown B.J. Inhibition of alloantigen-induced cytolytic T lymphocytes in vitro with (2R,5R)-6-heptyne-2,5-diamine, an irreversible inhibitor of ornithine decarboxylase. Cell. Immunol. 1988;111:443–450. doi: 10.1016/0008-8749(88)90107-4.
- Lampropoulou V., Sergushichev A., Bambouskova M., Nair S., Vincent E.E., Loginicheva E., Cervantes-Barragan L., Ma X., Huang S.C., Griss T., et al. Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation. Cell Metab. 2016;24:158–166. doi: 10.1016/j.cmet.2016.06.004.
- Murray P.J., Rathmell J., Pearce E. SnapShot: Immunometabolism. Cell Metab. 2015;22:190.e1. doi: 10.1016/j.cmet.2015.06.014.
- Kelly B., O‘Neill L.A. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015;25:771–784. doi: 10.1038/cr.2015.68.
- Nagaraj S., Youn J.I., Gabrilovich D.I. Reciprocal relationship between myeloid-derived suppressor cells and T cells. J. Immunol. 2013;191:17–23. doi: 10.4049/jimmunol.1300654.
- Youn J.I., Collazo M., Shalova I.N., Biswas S.K., Gabrilovich D.I. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J. Leukoc. Biol. 2012;91:167–181. doi: 10.1189/jlb.0311177.
- Rodriguez P.C., Ochoa A.C., Al-Khami A.A. Arginine Metabolism in Myeloid Cells Shapes Innate and Adaptive Immunity. Front. Immunol. 2017;8:93. doi: 10.3389/fimmu.2017.00093.
- Zhu M.Y., Iyo A., Piletz J.E., Regunathan S. Expression of human arginine decarboxylase, the biosynthetic enzyme for agmatine. Biochim. Biophys. Acta. 2004;1670:156–164. doi: 10.1016/j.bbagen.2003.11.006.
- Fuhrmann J., Thompson P.R. Protein Arginine Methylation and Citrullination in Epigenetic Regulation. ACS Chem. Biol. 2016;11:654–668. doi: 10.1021/acschembio.5b00942.
- Bronte V., Zanovello P. Regulation of immune responses by l-arginine metabolism. Nat. Rev. Immunol. 2005;5:641–654. doi: 10.1038/nri1668.
- Ye C., Geng Z., Dominguez D., Chen S., Fan J., Qin L., Long A., Zhang Y., Kuzel T.M., Zhang B. Targeting Ornithine Decarboxylase by α-Difluoromethylornithine Inhibits Tumor Growth by Impairing Myeloid-Derived Suppressor Cells. J. Immunol. 2016;196:915–923. doi: 10.4049/jimmunol.1500729.
- Ziv Y., Fazio V.W., Kitago K., Gupta M.K., Sawady J., Nishioka K. Effect of tamoxifen on 1,2-dimethylhydrazine-HCl-induced colon carcinogenesis in rats. Anticancer Res. 1997;17:803–810.
- Bowlin T.L., Hoeper B.J., Rosenberger A.L., Davis G.F., Sunkara P.S. Effects of three irreversible inhibitors of ornithine decarboxylase on macrophage-mediated tumoricidal activity and antitumor activity in B16F1 tumor-bearing mice. Cancer Res. 1990;50:4510–4514.
- Hayes C.S., Shicora A.C., Keough M.P., Snook A.E., Burns M.R., Gilmour S.K. Polyamine-blocking therapy reverses immunosuppression in the tumor microenvironment. Cancer Immunol. Res. 2014;2:274–285. doi: 10.1158/2326-6066.CIR-13-0120-T.
- Nagaraj S., Schrum A.G., Cho H.I., Celis E., Gabrilovich D.I. Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J. Immunol. 2010;184:3106–3116. doi: 10.4049/jimmunol.0902661.
- Sunderkotter C., Nikolic T., Dillon M.J., Van Rooijen N., Stehling M., Drevets D.A., Leenen P.J. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J. Immunol. 2004;172:4410–4417. doi: 10.4049/jimmunol.172.7.4410.
- Voisin M.B., Buzoni-Gatel D., Bout D., Velge-Roussel F. Both expansion of regulatory GR1+ CD11b+ myeloid cells and anergy of T lymphocytes participate in hyporesponsiveness of the lung-associated immune system during acute toxoplasmosis. Infect. Immun. 2004;72:5487–5492. doi: 10.1128/IAI.72.9.5487-5492.2004.
- Mencacci A., Montagnoli C., Bacci A., Cenci E., Pitzurra L., Spreca A., Kopf M., Sharpe A.H., Romani L. CD80+Gr-1+ myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis. J. Immunol. 2002;169:3180–3190. doi: 10.4049/jimmunol.169.6.3180.
- Garg A., Spector S.A. HIV type 1 gp120-induced expansion of myeloid derived suppressor cells is dependent on interleukin 6 and suppresses immunity. J. Infect. Dis. 2014;209:441–451. doi: 10.1093/infdis/jit469.
- Kumar V., Patel S., Tcyganov E., Gabrilovich D.I. The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Trends Immunol. 2016;37:208–220. doi: 10.1016/j.it.2016.01.004.
- Niino D., Komohara Y., Murayama T., Aoki R., Kimura Y., Hashikawa K., Kiyasu J., Takeuchi M., Suefuji N., Sugita Y., et al. Ratio of M2 macrophage expression is closely associated with poor prognosis for Angioimmunoblastic T-cell lymphoma (AITL) Pathol. Int. 2010;60:278–283. doi: 10.1111/j.1440-1827.2010.02514.x.
- Wang Y.C., He F., Feng F., Liu X.W., Dong G.Y., Qin H.Y., Hu X.B., Zheng M.H., Liang L., Feng L., et al. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 2010;70:4840–4849. doi: 10.1158/0008-5472.CAN-10-0269.
- Nagaraj S., Nelson A., Youn J.I., Cheng P., Quiceno D., Gabrilovich D.I. Antigen-specific CD4(+) T cells regulate function of myeloid-derived suppressor cells in cancer via retrograde MHC class II signaling. Cancer Res. 2012;72:928–938. doi: 10.1158/0008-5472.CAN-11-2863.
- Mills E.L., Kelly B., Logan A., Costa A.S.H., Varma M., Bryant C.E., Tourlomousis P., Dabritz J.H.M., Gottlieb E., Latorre I., et al. Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages. Cell. 2016;167:457–470. doi: 10.1016/j.cell.2016.08.064.
- Cao Y., Wang Q., Du Y., Liu F., Zhang Y., Feng Y., Jin F. l-arginine and docetaxel synergistically enhance anti-tumor immunity by modifying the immune status of tumor-bearing mice. Int. Immunopharmacol. 2016;35:7–14. doi: 10.1016/j.intimp.2016.03.002.
- He X., Lin H., Yuan L., Li B. Combination therapy with l-arginine and α-PD-L1 antibody boosts immune response against osteosarcoma in immunocompetent mice. Cancer Biol. Ther. 2017;18:94–100. doi: 10.1080/15384047.2016.1276136.
- Mondanelli G., Bianchi R., Pallotta M.T., Orabona C., Albini E., Iacono A., Belladonna M.L., Vacca C., Fallarino F., Macchiarulo A., et al. A Relay Pathway between Arginine and Tryptophan Metabolism Confers Immunosuppressive Properties on Dendritic Cells. Immunity. 2017;46:233–244. doi: 10.1016/j.immuni.2017.01.005.
- Rubin R.L., Burlingame R.W. Drug-induced autoimmunity: A disorder at the interface between metabolism and immunity. Biochem. Soc. Trans. 1991;19:153–159. doi: 10.1042/bst0190153.
- Rathmell J.C. Apoptosis and B cell tolerance. Curr. Dir. Autoimmun. 2003;6:38–60.
- Teti D., Visalli M., McNair H. Analysis of polyamines as markers of (patho)physiological conditions. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2002;781:107–149. doi: 10.1016/S1570-0232(02)00669-4.
- Karouzakis E., Gay R.E., Gay S., Neidhart M. Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheumatol. 2012;64:1809–1817. doi: 10.1002/art.34340.
- Pignata S., Di Luccia A., Lamanda R., Menchise A., D‘Agostino L. Interaction of putrescine with nuclear oligopeptides in the enterocyte-like Caco-2 cells. Digestion. 1999;60:255–261. doi: 10.1159/000007666.
- D‘Agostino L., Di Luccia A. Polyamines interact with DNA as molecular aggregates. Eur. J. Biochem. 2002;269:4317–4325. doi: 10.1046/j.1432-1033.2002.03128.x.
- D‘Agostino L., di Pietro M., Di Luccia A. Nuclear aggregates of polyamines are supramolecular structures that play a crucial role in genomic DNA protection and conformation. FEBS J. 2005;272:3777–3787. doi: 10.1111/j.1742-4658.2005.04782.x.
- Riboldi P., Gerosa M., Moroni G., Radice A., Allegri F., Sinico A., Tincani A., Meroni P.L. Anti-DNA antibodies: A diagnostic and prognostic tool for systemic lupus erythematosus? Autoimmunity. 2005;38:39–45. doi: 10.1080/08916930400022616.
- Fineschi S., Borghi M.O., Riboldi P., Gariglio M., Buzio C., Landolfo S., Cebecauer L., Tuchynova A., Rovensky J., Meroni P.L. Prevalence of autoantibodies against structure specific recognition protein 1 in systemic lupus erythematosus. Lupus. 2004;13:463–468. doi: 10.1191/0961203304lu1049oa.
- Casero R.A., Jr. Say what? The activity of the polyamine biosynthesis inhibitor difluoromethylornithine in chemoprevention is a result of reduced thymidine pools? Cancer Discov. 2013;3:975–977. doi: 10.1158/-13-0427.
- Ruan H., Hill J.R., Fatemie-Nainie S., Morris D.R. Cell-specific translational regulation of S-adenosylmethionine decarboxylase mRNA. Influence of the structure of the 5′ transcript leader on regulation by the upstream open reading frame. J. Biol. Chem. 1994;269:17905–17910.
- Ruan H., Shantz L.M., Pegg A.E., Morris D.R. The upstream open reading frame of the mRNA encoding S-adenosylmethionine decarboxylase is a polyamine-responsive translational control element. J. Biol. Chem. 1996;271:29576–29582. doi: 10.1074/jbc.271.47.29576.
- Bale S., Lopez M.M., Makhatadze G.I., Fang Q., Pegg A.E., Ealick S.E. Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. Biochemistry. 2008;47:13404–13417. doi: 10.1021/bi801732m.
Source: PubMed