#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

iNKT Cell Production of GM-CSF Controls


Invariant natural killer T (iNKT) cells are activated during infection, but how they limit microbial growth is unknown in most cases. We investigated how iNKT cells suppress intracellular Mycobacterium tuberculosis (Mtb) replication. When co-cultured with infected macrophages, iNKT cell activation, as measured by CD25 upregulation and IFNγ production, was primarily driven by IL-12 and IL-18. In contrast, iNKT cell control of Mtb growth was CD1d-dependent, and did not require IL-12, IL-18, or IFNγ. This demonstrated that conventional activation markers did not correlate with iNKT cell effector function during Mtb infection. iNKT cell control of Mtb replication was also independent of TNF and cell-mediated cytotoxicity. By dissociating cytokine-driven activation and CD1d-restricted effector function, we uncovered a novel mediator of iNKT cell antimicrobial activity: GM-CSF. iNKT cells produced GM-CSF in vitro and in vivo in a CD1d-dependent manner during Mtb infection, and GM-CSF was both necessary and sufficient to control Mtb growth. Here, we have identified GM-CSF production as a novel iNKT cell antimicrobial effector function and uncovered a potential role for GM-CSF in T cell immunity against Mtb.


Vyšlo v časopise: iNKT Cell Production of GM-CSF Controls. PLoS Pathog 10(1): e32767. doi:10.1371/journal.ppat.1003805
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003805

Souhrn

Invariant natural killer T (iNKT) cells are activated during infection, but how they limit microbial growth is unknown in most cases. We investigated how iNKT cells suppress intracellular Mycobacterium tuberculosis (Mtb) replication. When co-cultured with infected macrophages, iNKT cell activation, as measured by CD25 upregulation and IFNγ production, was primarily driven by IL-12 and IL-18. In contrast, iNKT cell control of Mtb growth was CD1d-dependent, and did not require IL-12, IL-18, or IFNγ. This demonstrated that conventional activation markers did not correlate with iNKT cell effector function during Mtb infection. iNKT cell control of Mtb replication was also independent of TNF and cell-mediated cytotoxicity. By dissociating cytokine-driven activation and CD1d-restricted effector function, we uncovered a novel mediator of iNKT cell antimicrobial activity: GM-CSF. iNKT cells produced GM-CSF in vitro and in vivo in a CD1d-dependent manner during Mtb infection, and GM-CSF was both necessary and sufficient to control Mtb growth. Here, we have identified GM-CSF production as a novel iNKT cell antimicrobial effector function and uncovered a potential role for GM-CSF in T cell immunity against Mtb.


Zdroje

1. BeckmanEM, PorcelliSA, MoritaCT, BeharSM, FurlongST, et al. (1994) Recognition of a lipid antigen by CD1-restricted alpha beta+ T cells. Nature 372: 691–694.

2. BeckmanEM, MelianA, BeharSM, SielingPA, ChatterjeeD, et al. (1996) CD1c restricts responses of mycobacteria-specific T cells. Evidence for antigen presentation by a second member of the human CD1 family. J Immunol 157: 2795–2803.

3. BendelacA, SavagePB, TeytonL (2007) The biology of NKT cells. Annu Rev Immunol 25: 297–336.

4. KinjoY, TupinE, WuD, FujioM, Garcia-NavarroR, et al. (2006) Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat Immunol 7: 978–986.

5. MattnerJ, DebordKL, IsmailN, GoffRD, CantuC3rd, et al. (2005) Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434: 525–529.

6. KinjoY, IllarionovP, VelaJL, PeiB, GirardiE, et al. (2011) Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria. Nat Immunol 12: 966–974.

7. BriglM, BryL, KentSC, GumperzJE, BrennerMB (2003) Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nat Immunol 4: 1230–1237.

8. PagetC, IvanovS, FontaineJ, RennesonJ, BlancF, et al. Interleukin-22 is produced by invariant natural killer T lymphocytes during influenza A virus infection: potential role in protection against lung epithelial damages. J Biol Chem 287: 8816–8829.

9. CohenNR, TatituriRV, RiveraA, WattsGF, KimEY, et al. (2012) Innate recognition of cell wall beta-glucans drives invariant natural killer T cell responses against fungi. Cell Host Microbe 10: 437–450.

10. BriglM, TatituriRV, WattsGF, BhowruthV, LeadbetterEA, et al. (2011) Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J Exp Med 208: 1163–1177.

11. NakamatsuM, YamamotoN, HattaM, NakasoneC, KinjoT, et al. (2007) Role of interferon-gamma in Valpha14+ natural killer T cell-mediated host defense against Streptococcus pneumoniae infection in murine lungs. Microbes Infect 9: 364–374.

12. MatsudaJL, MallevaeyT, Scott-BrowneJ, GapinL (2008) CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system. Curr Opin Immunol 20: 358–368.

13. NieuwenhuisEE, MatsumotoT, ExleyM, SchleipmanRA, GlickmanJ, et al. (2002) CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nat Med 8: 588–593.

14. ChackerianA, AltJ, PereraV, BeharSM (2002) Activation of NKT cells protects mice from tuberculosis. Infect Immun 70: 6302–6309.

15. Sada-OvalleI, SkoldM, TianT, BesraGS, BeharSM (2010) Alpha-galactosylceramide as a therapeutic agent for pulmonary Mycobacterium tuberculosis infection. Am J Respir Crit Care Med 182: 841–847.

16. GansertJL, KiesslerV, EngeleM, WittkeF, RollinghoffM, et al. (2003) Human NKT cells express granulysin and exhibit antimycobacterial activity. J Immunol 170: 3154–3161.

17. VenkataswamyMM, BaenaA, GoldbergMF, BricardG, ImJS, et al. (2009) Incorporation of NKT cell-activating glycolipids enhances immunogenicity and vaccine efficacy of Mycobacterium bovis bacillus Calmette-Guerin. J Immunol 183: 1644–1656.

18. Sada-OvalleI, ChibaA, GonzalesA, BrennerMB, BeharSM (2008) Innate invariant NKT cells recognize Mycobacterium tuberculosis-infected macrophages, produce interferon-gamma, and kill intracellular bacteria. PLoS Pathog 4: e1000239.

19. SutherlandJS, JeffriesDJ, DonkorS, WaltherB, HillPC, et al. (2009) High granulocyte/lymphocyte ratio and paucity of NKT cells defines TB disease in a TB-endemic setting. Tuberculosis (Edinb) 89: 398–404.

20. ImJS, KangTJ, LeeSB, KimCH, LeeSH, et al. (2008) Alteration of the relative levels of iNKT cell subsets is associated with chronic mycobacterial infections. Clin Immunol 127: 214–224.

21. MontoyaCJ, CatanoJC, RamirezZ, RugelesMT, WilsonSB, et al. (2008) Invariant NKT cells from HIV-1 or Mycobacterium tuberculosis-infected patients express an activated phenotype. Clin Immunol 127: 1–6.

22. BeharSM, DascherCC, GrusbyMJ, WangCR, BrennerMB (1999) Susceptibility of mice deficient in CD1D or TAP1 to infection with Mycobacterium tuberculosis. J Exp Med 189: 1973–1980.

23. D'SouzaCD, CooperAM, FrankAA, EhlersS, TurnerJ, et al. (2000) A novel nonclassic beta2-microglobulin-restricted mechanism influencing early lymphocyte accumulation and subsequent resistance to tuberculosis in the lung. Am J Respir Cell Mol Biol 23: 188–193.

24. SugawaraI, YamadaH, MizunoS, LiCY, NakayamaT, et al. (2002) Mycobacterial infection in natural killer T cell knockout mice. Tuberculosis (Edinb) 82: 97–104.

25. SousaAO, MazzaccaroRJ, RussellRG, LeeFK, TurnerOC, et al. (2000) Relative contributions of distinct MHC class I-dependent cell populations in protection to tuberculosis infection in mice. Proc Natl Acad Sci U S A 97: 4204–4208.

26. NagarajanNA, KronenbergM (2007) Invariant NKT cells amplify the innate immune response to lipopolysaccharide. J Immunol 178: 2706–2713.

27. FremondCM, YeremeevV, NicolleDM, JacobsM, QuesniauxVF, et al. (2004) Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88. J Clin Invest 114: 1790–1799.

28. JungYJ, LaCourseR, RyanL, NorthRJ (2002) Virulent but not avirulent Mycobacterium tuberculosis can evade the growth inhibitory action of a T helper 1-dependent, nitric oxide Synthase 2-independent defense in mice. J Exp Med 196: 991–998.

29. MartinCJ, BootyMG, RosebrockTR, Nunes-AlvesC, DesjardinsDM, et al. (2012) Efferocytosis is an innate antibacterial mechanism. Cell Host Microbe 12: 289–300.

30. FlynnJL, GoldsteinMM, ChanJ, TrieboldKJ, PfefferK, et al. (1995) Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 2: 561–572.

31. JayaramanP, Sada-OvalleI, NishimuraT, AndersonAC, KuchrooVK, et al. (2013) IL-1beta Promotes Antimicrobial Immunity in Macrophages by Regulating TNFR Signaling and Caspase-3 Activation. J Immunol 190: 4196–4204.

32. Mayer-BarberKD, BarberDL, ShenderovK, WhiteSD, WilsonMS, et al. (2010) Caspase-1 independent IL-1beta production is critical for host resistance to mycobacterium tuberculosis and does not require TLR signaling in vivo. J Immunol 184: 3326–3330.

33. KahnertA, SeilerP, SteinM, BandermannS, HahnkeK, et al. (2006) Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis. Eur J Immunol 36: 631–647.

34. WangX, BishopKA, HegdeS, RodenkirchLA, PikeJW, et al. (2012) Human invariant natural killer T cells acquire transient innate responsiveness via histone H4 acetylation induced by weak TCR stimulation. Journal of Experimental Medicine 987–1000.

35. DenisM, GhadirianE (1990) Granulocyte-macrophage colony-stimulating factor restricts growth of tubercle bacilli in human macrophages. Immunol Lett 24: 203–206.

36. BermudezLE, YoungLS (1990) Recombinant granulocyte-macrophage colony-stimulating factor activates human macrophages to inhibit growth or kill Mycobacterium avium complex. J Leukoc Biol 48: 67–73.

37. DenisM (1991) Tumor necrosis factor and granulocyte macrophage-colony stimulating factor stimulate human macrophages to restrict growth of virulent Mycobacterium avium and to kill avirulent M. avium: killing effector mechanism depends on the generation of reactive nitrogen intermediates. J Leukoc Biol 49: 380–387.

38. BarnesPF, LuS, AbramsJS, WangE, YamamuraM, et al. (1993) Cytokine production at the site of disease in human tuberculosis. Infect Immun 61: 3482–3489.

39. BhattacharyyaS, SinglaR, DeyAB, PrasadHK (1999) Dichotomy of cytokine profiles in patients and high-risk healthy subjects exposed to tuberculosis. Infect Immun 67: 5597–5603.

40. HoftDF, WorkuS, KampmannB, WhalenCC, EllnerJJ, et al. (2002) Investigation of the relationships between immune-mediated inhibition of mycobacterial growth and other potential surrogate markers of protective Mycobacterium tuberculosis immunity. J Infect Dis 186: 1448–1457.

41. CowleySC, ElkinsKL (2003) CD4+ T cells mediate IFN-gamma-independent control of Mycobacterium tuberculosis infection both in vitro and in vivo. J Immunol 171: 4689–4699.

42. CanadayDH, WilkinsonRJ, LiQ, HardingCV, SilverRF, et al. (2001) CD4(+) and CD8(+) T cells kill intracellular Mycobacterium tuberculosis by a perforin and Fas/Fas ligand-independent mechanism. J Immunol 167: 2734–2742.

43. WoodworthJS, WuY, BeharSM (2008) Mycobacterium tuberculosis-specific CD8+ T cells require perforin to kill target cells and provide protection in vivo. J Immunol 181: 8595–8603.

44. Gonzalez-JuarreroM, HattleJM, IzzoA, Junqueira-KipnisAP, ShimTS, et al. (2005) Disruption of granulocyte macrophage-colony stimulating factor production in the lungs severely affects the ability of mice to control Mycobacterium tuberculosis infection. J Leukoc Biol 77: 914–922.

45. SzeligaJ, DanielDS, YangCH, Sever-ChroneosZ, JagannathC, et al. (2008) Granulocyte-macrophage colony stimulating factor-mediated innate responses in tuberculosis. Tuberculosis (Edinb) 88: 7–20.

46. RosenLB, FreemanAF, YangLM, JutivorakoolK, OlivierKN, et al. (2013) Anti-GM-CSF Autoantibodies in Patients with Cryptococcal Meningitis. J Immunol 190: 3959–3966.

47. HegdeS, ChenX, KeatonJM, ReddingtonF, BesraGS, et al. (2007) NKT cells direct monocytes into a DC differentiation pathway. J Leukoc Biol 81: 1224–1235.

48. FujiiS, ShimizuK, SmithC, BonifazL, SteinmanRM (2003) Activation of natural killer T cells by alpha-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J Exp Med 198: 267–279.

49. CohenNR, BrennanPJ, ShayT, WattsGF, BriglM, et al. (2012) Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells. Nat Immunol 14: 90–99.

50. BendelacA, HunzikerRD, LantzO (1996) Increased interleukin 4 and immunoglobulin E production in transgenic mice overexpressing NK1 T cells. J Exp Med 184: 1285–1293.

51. ExleyMA, BigleyNJ, ChengO, ShaulovA, TahirSM, et al. (2003) Innate immune response to encephalomyocarditis virus infection mediated by CD1d. Immunology 110: 519–526.

52. AdachiO, KawaiT, TakedaK, MatsumotoM, TsutsuiH, et al. (1998) Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9: 143–150.

53. ChibaA, CohenN, BriglM, BrennanPJ, BesraGS, et al. (2009) Rapid and reliable generation of invariant natural killer T-cell lines in vitro. Immunology 128: 324–333.

54. ParkSH, RoarkJH, BendelacA (1998) Tissue-specific recognition of mouse CD1 molecules. J Immunol 160: 3128–3134.

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2014 Číslo 1
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#