Redundant Notch1 and Notch2 Signaling Is Necessary for IFNγ Secretion by T Helper 1 Cells During Infection with
The protective immune response to intracellular parasites involves in most cases the differentiation of IFNγ-secreting CD4+ T helper (Th) 1 cells. Notch receptors regulate cell differentiation during development but their implication in the polarization of peripheral CD4+ T helper 1 cells is not well understood. Of the four Notch receptors, only Notch1 (N1) and Notch2 (N2) are expressed on activated CD4+ T cells. To investigate the role of Notch in Th1 cell differentiation following parasite infection, mice with T cell-specific gene ablation of N1, N2 or both (N1N2ΔCD4Cre) were infected with the protozoan parasite Leishmania major. N1N2ΔCD4Cre mice, on the C57BL/6 L. major-resistant genetic background, developed unhealing lesions and uncontrolled parasitemia. Susceptibility correlated with impaired secretion of IFNγ by draining lymph node CD4+ T cells and increased secretion of the IL-5 and IL-13 Th2 cytokines. Mice with single inactivation of N1 or N2 in their T cells were resistant to infection and developed a protective Th1 immune response, showing that CD4+ T cell expression of N1 or N2 is redundant in driving Th1 differentiation. Furthermore, we show that Notch signaling is required for the secretion of IFNγ by Th1 cells. This effect is independent of CSL/RBP-Jκ, the major effector of Notch receptors, since L. major-infected mice with a RBP-Jκ deletion in their T cells were able to develop IFNγ-secreting Th1 cells, kill parasites and heal their lesions. Collectively, we demonstrate here a crucial role for RBP-Jκ-independent Notch signaling in the differentiation of a functional Th1 immune response following L. major infection.
Vyšlo v časopise:
Redundant Notch1 and Notch2 Signaling Is Necessary for IFNγ Secretion by T Helper 1 Cells During Infection with. PLoS Pathog 8(3): e32767. doi:10.1371/journal.ppat.1002560
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002560
Souhrn
The protective immune response to intracellular parasites involves in most cases the differentiation of IFNγ-secreting CD4+ T helper (Th) 1 cells. Notch receptors regulate cell differentiation during development but their implication in the polarization of peripheral CD4+ T helper 1 cells is not well understood. Of the four Notch receptors, only Notch1 (N1) and Notch2 (N2) are expressed on activated CD4+ T cells. To investigate the role of Notch in Th1 cell differentiation following parasite infection, mice with T cell-specific gene ablation of N1, N2 or both (N1N2ΔCD4Cre) were infected with the protozoan parasite Leishmania major. N1N2ΔCD4Cre mice, on the C57BL/6 L. major-resistant genetic background, developed unhealing lesions and uncontrolled parasitemia. Susceptibility correlated with impaired secretion of IFNγ by draining lymph node CD4+ T cells and increased secretion of the IL-5 and IL-13 Th2 cytokines. Mice with single inactivation of N1 or N2 in their T cells were resistant to infection and developed a protective Th1 immune response, showing that CD4+ T cell expression of N1 or N2 is redundant in driving Th1 differentiation. Furthermore, we show that Notch signaling is required for the secretion of IFNγ by Th1 cells. This effect is independent of CSL/RBP-Jκ, the major effector of Notch receptors, since L. major-infected mice with a RBP-Jκ deletion in their T cells were able to develop IFNγ-secreting Th1 cells, kill parasites and heal their lesions. Collectively, we demonstrate here a crucial role for RBP-Jκ-independent Notch signaling in the differentiation of a functional Th1 immune response following L. major infection.
Zdroje
1. RadtkeFFasnachtNMacdonaldHR 2010 Notch signaling in the immune system. Immunity 32 14 27
2. SandyARMaillardI 2009 Notch signaling in the hematopoietic system. Expert Opin Biol Ther 9 1383 1398
3. OsipoCGoldeTEOsborneBAMieleLA 2008 Off the beaten pathway: the complex cross talk between Notch and NF-kappaB. Lab Invest 88 11 17
4. KopanRIlaganMX 2009 The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137 216 233
5. AmsenDAntovAFlavellRA 2009 The different faces of Notch in T-helper-cell differentiation. Nat Rev Immunol 9 116 124
6. MinterLMTurleyDMDasPShinHMJoshiI 2005 Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nat Immunol 6 680 688
7. MaekawaYTsukumoSChibaSHiraiHHayashiY 2003 Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells. Immunity 19 549 559
8. AmsenDBlanderJMLeeGRTanigakiKHonjoT 2004 Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117 515 526
9. Tacchini-CottierFAllenbachCOttenLARadtkeF 2004 Notch1 expression on T cells is not required for CD4+ T helper differentiation. Eur J Immunol 34 1588 1596
10. TuLFangTCArtisDShestovaOProssSE 2005 Notch signaling is an important regulator of type 2 immunity. J Exp Med 202 1037 1042
11. SkokosDNussenzweigMC 2007 CD8− DCs induce IL-12-independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS. J Exp Med 204 1525 1531
12. SunJKrawczykCJPearceEJ 2008 Suppression of Th2 cell development by Notch ligands Delta1 and Delta4. J Immunol 180 1655 1661
13. OngCTSedyJRMurphyKMKopanR 2008 Notch and presenilin regulate cellular expansion and cytokine secretion but cannot instruct Th1/Th2 fate acquisition. PLoS One 3 e2823
14. WorsleyAGLeibundGut-LandmannSSlackEPhngLKGerhardtH 2008 Dendritic cell expression of the Notch ligand jagged2 is not essential for Th2 response induction in vivo. Eur J Immunol 38 1043 1049
15. SacksDNoben-TrauthN 2002 The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol 2 845 858
16. FioriniEMerckEWilsonAFerreroIJiangW 2009 Dynamic regulation of notch 1 and notch 2 surface expression during T cell development and activation revealed by novel monoclonal antibodies. J Immunol 183 7212 7222
17. MatthewsDJEmsonCLMcKenzieGJJolinHEBlackwellJM 2000 IL-13 is a susceptibility factor for Leishmania major infection. J Immunol 164 1458 1462
18. Perona-WrightGMohrsKMohrsM 2010 Sustained signaling by canonical helper T cell cytokines throughout the reactive lymph node. Nat Immunol 11 520 526
19. Revaz-BretonMRonetCIvesATorreYHMasinaS 2010 The MyD88 protein 88 pathway is differently involved in immune responses induced by distinct substrains of Leishmania major. Eur J Immunol 40 1697 1707
20. O'SheaJJPaulWE 2010 Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327 1098 1102
21. FangTCYashiro-OhtaniYDel BiancoCKnoblockDMBlacklowSC 2007 Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 27 100 110
22. SanalkumarRDhaneshSBJamesJ 2010 Non-canonical activation of Notch signaling/target genes in vertebrates. Cell Mol Life Sci 67 2957 2968
23. ShinHMMinterLMChoOHGottipatiSFauqAH 2006 Notch1 augments NF-kappaB activity by facilitating its nuclear retention. Embo J 25 129 138
24. ArtisDSpeirsKJoyceKGoldschmidtMCaamanoJ 2003 NF-kappa B1 is required for optimal CD4+ Th1 cell development and resistance to Leishmania major. J Immunol 170 1995 2003
25. MohrsKWakilAEKilleenNLocksleyRMMohrsM 2005 A two-step process for cytokine production revealed by IL-4 dual-reporter mice. Immunity 23 419 429
26. WangZEReinerSLZhengSDaltonDKLocksleyRM 1994 CD4+ effector cells default to the Th2 pathway in interferon gamma-deficient mice infected with Leishmania major. J Exp Med 179 1367 1371
27. TanakaSTsukadaJSuzukiWHayashiKTanigakiK 2006 The interleukin-4 enhancer CNS-2 is regulated by Notch signals and controls initial expression in NKT cells and memory-type CD4 T cells. Immunity 24 689 701
28. ElyamanWBradshawEMWangYOukkaMKivisakkP 2007 JAGGED1 and delta1 differentially regulate the outcome of experimental autoimmune encephalomyelitis. J Immunol 179 5990 5998
29. KrawczykCMSunJPearceEJ 2008 Th2 differentiation is unaffected by Jagged2 expression on dendritic cells. J Immunol 180 7931 7937
30. FakiolaMMillerENFadlMMohamedHSJamiesonSE 2011 Genetic and functional evidence implicating DLL1 as the gene that influences susceptibility to visceral leishmaniasis at chromosome 6q27. J Infect Dis 204 467 477
31. RadtkeFWilsonAStarkGBauerMvan MeerwijkJ 1999 Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10 547 558
32. BesseyriasVFioriniEStroblLJZimber-StroblUDumortierA 2007 Hierarchy of Notch-Delta interactions promoting T cell lineage commitment and maturation. J Exp Med 204 331 343
33. TanigakiKHanHYamamotoNTashiroKIkegawaM 2002 Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nat Immunol 3 443 450
34. LeePPFitzpatrickDRBeardCJessupHKLeharS 2001 A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15 763 774
35. YangGLiLVolkAEmmellEPetleyT 2005 Therapeutic dosing with anti-interleukin-13 monoclonal antibody inhibits asthma progression in mice. J Pharmacol Exp Ther 313 8 15
36. OttenLATacchini-CottierFLohoffMAnnunziatoFCosmiL 2003 Deregulated MHC class II transactivator expression leads to a strong Th2 bias in CD4+ T lymphocytes. J Immunol 170 1150 1157
37. CharmoyMMegnekouRAllenbachCZweifelCPerezC 2007 Leishmania major induces distinct neutrophil phenotypes in mice that are resistant or susceptible to infection. J Leukoc Biol 82 288 299
38. MenziesFMHenriquezFLAlexanderJRobertsCW 2010 Sequential expression of macrophage anti-microbial/inflammatory and wound healing markers following innate, alternative and classical activation. Clin Exp Immunol 160 369 379
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2012 Číslo 3
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- A Foot in the Door for Dermatophyte Research
- An Entomopathogenic Nematode by Any Other Name
- New Insights into spp.: A Potential Link with Irritable Bowel Syndrome
- Short ORF-Dependent Ribosome Shunting Operates in an RNA Picorna-Like Virus and a DNA Pararetrovirus that Cause Rice Tungro Disease