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Regulation of invariant NKT cell development and function by a 0.14 Mbp locus on chromosome 1: a possible role for Fcgr3

Genes & Immunity volume 20, pages 261–272 (2019)Cite this article

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Abstract

Invariant NKT (iNKT) cells are tissue-resident innate-like T cells critical to the host immune response. We previously identified a 6.6 Mbp region on chromosome 1 as a major regulator of iNKT cell number and function in C57BL/6 and 129X1/SvJ mice. Here, we fine-mapped this locus by assessing the iNKT cell response to alpha-galactosylceramide (αGalCer) in a series of B6.129 congenic lines. This analysis revealed the presence of at least two genetic elements that regulate iNKT cell cytokine production in response to αGalCer. While one of these genetic elements mapped to the B6.129c6 interval containing Slam genes, the dominant regulator in this region mapped to the 0.14 Mbp B6.129c3 interval. In addition, we found that numbers of thymic iNKT cells and DP thymocytes were significantly lower in B6.129c3 mice, indicating that this interval also regulates iNKT cell development. Candidate gene analysis revealed a fivefold increase in Fcgr3 expression in B6.129c3 iNKT cells, and we observed increased expression of FcγR3 protein on B6.129c3 iNKT cells, NK cells, and neutrophils. These data identify the B6.129c3 interval as a novel locus regulating the response of iNKT cells to glycosphingolipid, revealing a link between this phenotype and a polymorphism that regulates Fcgr3 expression.

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References

  1. Godfrey DI, Rossjohn J. New ways to turn on NKT cells. J Exp Med. 2011;208:1121–5.

    Article  CAS  Google Scholar 

  2. Gumperz JE, Brenner MB. CD1-specific T cells in microbial immunity. Curr Opin Immunol. 2001;13:471–8.

    Article  CAS  Google Scholar 

  3. Behar SM, Porcelli SA. CD1-restricted T cells in host defense to infectious diseases. Curr Top Microbiol Immunol. 2007;314:215–50.

    CAS  PubMed  Google Scholar 

  4. Spada FM, Koezuka Y, Porcelli SA. CD1d-restricted recognition of synthetic glycolipid antigens by human natural killer T cells. J Exp Med. 1998;188:1529–34.

    Article  CAS  Google Scholar 

  5. Pellicci DG, Patel O, Kjer-Nielsen L, Pang SS, Sullivan LC, Kyparissoudis K, et al. Differential recognition of CD1d-alpha-galactosyl ceramide by the V beta 8.2 and V beta 7 semi-invariant NKT T cell receptors. Immunity. 2009;31:47–59.

    Article  CAS  Google Scholar 

  6. Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, et al. CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science. 1997;278:1626–9.

    Article  CAS  Google Scholar 

  7. Wieland Brown LC, Penaranda C, Kashyap PC, Williams BB, Clardy J, Kronenberg M, et al. Production of alpha-galactosylceramide by a prominent member of the human gut microbiota. PLoS Biol. 2013;11:e1001610.

    Article  Google Scholar 

  8. Borg NA, Wun KS, Kjer-Nielsen L, Wilce MC, Pellicci DG, Koh R, et al. CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature. 2007;448:44–9.

    Article  CAS  Google Scholar 

  9. Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Sato H, et al. Natural killer-like nonspecific tumor cell lysis mediated by specific ligand-activated Valpha14 NKT cells. Proc Natl Acad Sci USA. 1998;95:5690–3.

    Article  CAS  Google Scholar 

  10. Takahashi T, Nieda M, Koezuka Y, Nicol A, Porcelli SA, Ishikawa Y, et al. Analysis of human V alpha 24+ CD4+ NKT cells activated by alpha- glycosylceramide-pulsed monocyte-derived dendritic cells. J Immunol. 2000;164:4458–64.

    Article  CAS  Google Scholar 

  11. Koch M, Stronge VS, Shepherd D, Gadola SD, Mathew B, Ritter G, et al. The crystal structure of human CD1d with and without alpha-galactosylceramide. Nat Immunol. 2005;6:819–26.

    Article  CAS  Google Scholar 

  12. Yoshimoto T, Paul WE. CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3. J Exp Med. 1994;179:1285–95.

    Article  CAS  Google Scholar 

  13. Coquet JM, Chakravarti S, Kyparissoudis K, McNab FW, Pitt LA, McKenzie BS, et al. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population. Proc Natl Acad Sci USA. 2008;105:11287–92.

    Article  CAS  Google Scholar 

  14. Gumperz JE, Miyake S, Yamamura T, Brenner MB. Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J Exp Med. 2002;195:625–36.

    Article  CAS  Google Scholar 

  15. Sada-Ovalle I, Chiba A, Gonzales A, Brenner MB, Behar SM. Innate invariant NKT cells recognize Mycobacterium tuberculosis-infected macrophages, produce interferon-gamma, and kill intracellular bacteria. PLoS Pathog. 2008;4:e1000239.

    Article  Google Scholar 

  16. Kitamura H, Iwakabe K, Yahata T, Nishimura S, Ohta A, Ohmi Y, et al. The natural killer T (NKT) cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J Exp Med. 1999;189:1121–8.

    Article  CAS  Google Scholar 

  17. Hermans IF, Silk JD, Gileadi U, Salio M, Mathew B, Ritter G, et al. NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol. 2003;171:5140–7.

    Article  CAS  Google Scholar 

  18. Eberl G, MacDonald HR. Selective induction of NK cell proliferation and cytotoxicity by activated NKT cells. Eur J Immunol. 2000;30:985–92.

    Article  CAS  Google Scholar 

  19. Carnaud C, Lee D, Donnars O, Park SH, Beavis A, Koezuka Y, et al. Cutting edge: cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. J Immunol. 1999;163:4647–50.

    CAS  PubMed  Google Scholar 

  20. Borg ZD, Benoit PJ, Lilley GW, Aktan I, Chant A, DeVault VL, et al. Polymorphisms in the CD1d promoter that regulate CD1d gene expression are associated with impaired NKT cell development. J Immunol. 2014;192:189–99.

    Article  CAS  Google Scholar 

  21. Chen YG, Tsaih SW, Serreze DV. Genetic control of murine invariant natural killer T-cell development dynamically differs dependent on the examined tissue type. Genes Immun. 2012;13:164–74.

    Article  CAS  Google Scholar 

  22. Rymarchyk SL, Lowenstein H, Mayette J, Foster SR, Damby DE, Howe IW, et al. Widespread natural variation in murine natural killer T-cell number and function. Immunology. 2008;125:331–43.

    Article  CAS  Google Scholar 

  23. Lee YJ, Wang H, Starrett GJ, Phuong V, Jameson SC, Hogquist KA. Tissue-specific distribution of iNKT cells impacts their cytokine response. Immunity. 2015;43:566–78.

    Article  CAS  Google Scholar 

  24. Hammond KJ, Pellicci DG, Poulton LD, Naidenko OV, Scalzo AA, Baxter AG, et al. CD1d-restricted NKT cells: an interstrain comparison. J Immunol. 2001;167:1164–73.

    Article  CAS  Google Scholar 

  25. Gombert JM, Herbelin A, Tancrede-Bohin E, Dy M, Carnaud C, Bach JF. Early quantitative and functional deficiency of NK1+ -like thymocytes in the NOD mouse. Eur J Immunol. 1996;26:2989–98.

    Article  CAS  Google Scholar 

  26. Benoit P, Sigounas VY, Thompson JL, van Rooijen N, Poynter ME, Wargo MJ, et al. The role of CD1d-restricted NKT cells in the clearance of Pseudomonas aeruginosa from the lung is dependent on the host genetic background. Infect Immun. 2015;83:2557–65.

    Article  CAS  Google Scholar 

  27. Tupin E, Benhnia MR, Kinjo Y, Patsey R, Lena CJ, Haller MC, et al. NKT cells prevent chronic joint inflammation after infection with Borrelia burgdorferi. Proc Natl Acad Sci USA. 2008;105:19863–8.

    Article  CAS  Google Scholar 

  28. Olson CM Jr, Bates TC, Izadi H, Radolf JD, Huber SA, Boyson JE, et al. Local production of IFN-gamma by invariant NKT cells modulates acute Lyme carditis. J Immunol. 2009;182:3728–34.

    Article  CAS  Google Scholar 

  29. Jordan MA, Fletcher JM, Pellicci D, Baxter AG. Slamf1, the NKT cell control gene Nkt1. J Immunol. 2007;178:1618–27.

    Article  CAS  Google Scholar 

  30. Esteban LM, Tsoutsman T, Jordan MA, Roach D, Poulton LD, Brooks A, Naidenko OV, Sidobre S, Godfrey DI, Baxter AG. Genetic control of NKT cell numbers maps to major diabetes and lupus loci. J Immunol. 2003;171:2873–8.

    Article  CAS  Google Scholar 

  31. Aktan I, Chant A, Borg ZD, Damby DE, Leenstra PC, Lilley GW, et al. Slam haplotypes modulate the response to lipopolysaccharide in vivo through control of NKT cell number and function. J Immunol. 2010;185:144–56.

    Article  CAS  Google Scholar 

  32. Fletcher JM, Jordan MA, Snelgrove SL, Slattery RM, Dufour FD, Kyparissoudis K, et al. Congenic analysis of the NKT cell control gene Nkt2 implicates the peroxisomal protein Pxmp4. J Immunol. 2008;181:3400–12.

    Article  CAS  Google Scholar 

  33. Wesley JD, Tessmer MS, Paget C, Trottein F, Brossay LA. Y chromosome-linked factor impairs NKT development. J Immunol. 2007;179:3480–7.

    Article  CAS  Google Scholar 

  34. Zhang F, Liang Z, Matsuki N, Van Kaer L, Joyce S, Wakeland EK, et al. A murine locus on chromosome 18 controls NKT cell homeostasis and the cell differentiation. J Immunol. 2003;171:4613–20.

    Article  CAS  Google Scholar 

  35. Araujo LM, Puel A, Gouarin C, Hameg A, Mevel JC, Koezuka Y, et al. NKT lymphocyte ontogeny and function are impaired in low antibody- producer Biozzi mice: gene mapping in the interval-specific congenic strains raised for immunomodulatory genes. Int Immunol. 2000;12:1613–22.

    Article  CAS  Google Scholar 

  36. Rocha-Campos AC, Melki R, Zhu R, Deruytter N, Damotte D, Dy M, et al. Genetic and functional analysis of the Nkt1 locus using congenic NOD mice: improved Valpha14-NKT cell performance but failure to protect against type 1 diabetes. Diabetes. 2006;55:1163–70.

    Article  CAS  Google Scholar 

  37. Griewank K, Borowski C, Rietdijk S, Wang N, Julien A, Wei DG, et al. Homotypic interactions mediated by Slamf1 and Slamf6 receptors control NKT cell lineage development. Immunity. 2007;27:751–62.

    Article  CAS  Google Scholar 

  38. Wandstrat AE, Nguyen C, Limaye N, Chan AY, Subramanian S, Tian XH, et al. Association of extensive polymorphisms in the SLAM/CD2 gene cluster with murine lupus. Immunity. 2004;21:769–80.

    Article  CAS  Google Scholar 

  39. Edberg JC, Langefeld CD, Wu J, Moser KL, Kaufman KM, Kelly J, et al. Genetic linkage and association of Fc gamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus. Arthritis Rheum. 2002;46:2132–40.

    Article  CAS  Google Scholar 

  40. Morel L, Blenman KR, Croker BP, Wakeland EK. The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes. Proc Natl Acad Sci USA. 2001;98:1787–92.

    Article  CAS  Google Scholar 

  41. Baxter AG, Kinder SJ, Hammond KJ, Scollay R, Godfrey DI. Association between alphabetaTCR+CD4-CD8- T-cell deficiency and IDDM in NOD/Lt mice. Diabetes. 1997;46:572–82.

    Article  CAS  Google Scholar 

  42. Cardell SL. The natural killer T lymphocyte: a player in the complex regulation of autoimmune diabetes in non-obese diabetic mice. Clin Exp Immunol. 2006;143:194–202.

    Article  CAS  Google Scholar 

  43. Esteban LM, Tsoutsman T, Jordan MA, Roach D, Poulton LD, Brooks A, et al. Genetic control of NKT cell numbers maps to major diabetes and lupus loci. J Immunol. 2003;171:2873–8.

    Article  CAS  Google Scholar 

  44. Jordan MA, Fletcher JM, Jose R, Chowdhury S, Gerlach N, Allison J, et al. Role of SLAM in NKT cell development revealed by transgenic complementation in NOD mice. J Immunol. 2011;186:3953–65.

    Article  CAS  Google Scholar 

  45. Lee YJ, Holzapfel KL, Zhu J, Jameson SC, Hogquist KA. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat Immunol. 2013;14:1146–54.

    Article  CAS  Google Scholar 

  46. Heng TS, Painter MW, Immunological Genome Project Consortium. The Immunological Genome Project: networks of gene expression in immune cells. Nat Immunol. 2008;9:1091–4.

    Article  CAS  Google Scholar 

  47. Kim HY, Kim S, Chung DH. FcgammaRIII engagement provides activating signals to NKT cells in antibody-induced joint inflammation. J Clin Invest. 2006;116:2484–92.

    Article  CAS  Google Scholar 

  48. Nieuwenhuis EE, Matsumoto T, Exley M, Schleipman RA, Glickman J, Bailey DT, et al. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nat Med. 2002;8:588–93.

    Article  CAS  Google Scholar 

  49. Stevenson MM, Kondratieva TK, Apt AS, Tam MF, Skamene E. In vitro and in vivo T cell responses in mice during bronchopulmonary infection with mucoid Pseudomonas aeruginosa. Clin Exp Immunol. 1995;99:98–105.

    Article  CAS  Google Scholar 

  50. Jordan MA, Fletcher J, Baxter AG. Genetic control of NKT cell numbers. Immunol Cell Biol. 2004;82:276–84.

    Article  CAS  Google Scholar 

  51. Godfrey DI, Kinder SJ, Silvera P, Baxter AG. Flow cytometric study of T cell development in NOD mice reveals a deficiency in alphabetaTCR+CDR-CD8- thymocytes. J Autoimmun. 1997;10:279–85.

    Article  CAS  Google Scholar 

  52. Nimmerjahn F, Ravetch JV. Fc-receptors as regulators of immunity. Adv Immunol. 2007;96:179–204.

    Article  CAS  Google Scholar 

  53. Dreos R, Ambrosini G, Groux R, Cavin Perier R, Bucher P. The eukaryotic promoter database in its 30th year: focus on non-vertebrate organisms. Nucleic Acids Res. 2017;45(D1):D51–D5.

    Article  CAS  Google Scholar 

  54. Park-Min KH, Serbina NV, Yang W, Ma X, Krystal G, Neel BG, et al. FcgammaRIII-dependent inhibition of interferon-gamma responses mediates suppressive effects of intravenous immune globulin. Immunity. 2007;26:67–78.

    Article  CAS  Google Scholar 

  55. Araujo LM, Chauvineau A, Zhu R, Diem S, Bourgeois EA, Levescot A, et al. Cutting edge: intravenous Ig inhibits invariant NKT cell-mediated allergic airway inflammation through FcgammaRIIIA-dependent mechanisms. J Immunol. 2011;186:3289–93.

    Article  CAS  Google Scholar 

  56. Sandor M, Galon J, Takacs L, Tatsumi Y, Mueller AL, Sautes C, et al. An alternative Fc gamma-receptor ligand: potential role in T-cell development. Proc Natl Acad Sci USA. 1994;91:12857–61.

    Article  CAS  Google Scholar 

  57. Rodewald HR, Moingeon P, Lucich JL, Dosiou C, Lopez P, Reinherz EL. A population of early fetal thymocytes expressing Fc gamma RII/III contains precursors of T lymphocytes and natural killer cells. Cell. 1992;69:139–50.

    Article  CAS  Google Scholar 

  58. Shores E, Flamand V, Tran T, Grinberg A, Kinet JP, Love PE. Fc epsilon RI gamma can support T cell development and function in mice lacking endogenous TCR zeta-chain. J Immunol. 1997;159:222–30.

    CAS  PubMed  Google Scholar 

  59. Flamand V, Shores EW, Tran T, Huang K, Lee E, Grinberg A, et al. Delayed maturation of CD4- CD8- Fc gamma RII/III+ T and natural killer cell precursors in Fc epsilon RI gamma transgenic mice. J Exp Med. 1996;184:1725–35.

    Article  CAS  Google Scholar 

  60. Georgiev H, Ravens I, Benarafa C, Forster R, Bernhardt G. Distinct gene expression patterns correlate with developmental and functional traits of iNKT subsets. Nat Commun. 2016;7:13116.

    Article  CAS  Google Scholar 

  61. Renkema GH, Wortmann SB, Smeets RJ, Venselaar H, Antoine M, Visser G, et al. SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors. Eur J Hum Genet. 2015;23:202–9.

    Article  CAS  Google Scholar 

  62. Bader E, Migliorini A, Gegg M, Moruzzi N, Gerdes J, Roscioni SS, et al. Identification of proliferative and mature beta-cells in the islets of Langerhans. Nature. 2016;535:430–4.

    Article  CAS  Google Scholar 

  63. Frias AB, Jr, Buechel HM, Neupane A, D’Cruz LM. Invariant natural killer T-cell development and function with loss of microRNA-155. Immunology. 2017;153:238–45.

    Article  Google Scholar 

  64. Burocchi A, Pittoni P, Tili E, Rigoni A, Costinean S, Croce CM, et al. Regulated expression of miR-155 is required for iNKT cell development. Front Immunol. 2015;6:140.

    Article  Google Scholar 

  65. Fedeli M, Riba M, Garcia Manteiga JM, Tian L, Vigano V, Rossetti G, et al. miR-17 approximately 92 family clusters control iNKT cell ontogenesis via modulation of TGF-beta signaling. Proc Natl Acad Sci USA. 2016;113:E8286–E95.

    Article  CAS  Google Scholar 

  66. Castellano L, Stebbing J. Deep sequencing of small RNAs identifies canonical and non-canonical miRNA and endogenous siRNAs in mammalian somatic tissues. Nucleic Acids Res. 2013;41:3339–51.

    Article  CAS  Google Scholar 

  67. Meunier J, Lemoine F, Soumillon M, Liechti A, Weier M, Guschanski K, et al. Birth and expression evolution of mammalian microRNA genes. Genome Res. 2013;23:34–45.

    Article  CAS  Google Scholar 

  68. Aken BL, Ayling S, Barrell D, Clarke L, Curwen V, Fairley S, et al. The Ensembl gene annotation system. Database. 2016;2016:baw093.

    Article  Google Scholar 

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Acknowledgements

We thank Roxana del Rio Guerra for help with cell sorting, and Camarie Spear for technical assistance. We also thank Dimitry Krementsov (University of Vermont) for providing neural tissue cDNA. The flow cytometry data were obtained at the Harry Hood Bassett Flow Cytometry and Cell Sorting Facility, Larner College of Medicine at the University of Vermont and was supported by NIH S10OD018175 (JEB). We acknowledge the NIH Tetramer Core Facility (contract HHSN272201300006C) for provision of mouse CD1d/PBS57 tetramers. The qPCR analysis was performed at the Larner College of Medicine Integrated Genomics Core, and we thank Jessica Hoffman for her technical assistance. This work was supported by NIH R21AI1199774 (JEB), T32 AI055402 (Ralph Budd, PI, VLD trainee) and RO1 HL133920 (MEP).

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  1. Department of Surgery, University of Vermont Larner College of Medicine, Burlington, VT, USA

    Victoria L. DeVault, Murisa Malagic, Linda Mei, Oliver Dienz, Graham W. J. Lilley, Patrick Benoit, Somen K. Mistri, Shawn C. Musial & Jonathan E. Boyson

  2. Cellular, Molecular, and Biomedical Sciences Program, University of Vermont, Burlington, VT, USA

    Victoria L. DeVault, Somen K. Mistri, Matthew E. Poynter & Jonathan E. Boyson

  3. Division of Pulmonary Disease and Critical Care, Department of Medicine, Vermont Lung Center, University of Vermont Larner College of Medicine, Burlington, VT, USA

    Jennifer L. Ather & Matthew E. Poynter

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  1. Victoria L. DeVault
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DeVault, V.L., Malagic, M., Mei, L. et al. Regulation of invariant NKT cell development and function by a 0.14 Mbp locus on chromosome 1: a possible role for Fcgr3. Genes Immun 20, 261–272 (2019). https://doi.org/10.1038/s41435-018-0031-2

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