Home LiteratureArticle Details
PMID: 16226507 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

A two-step process for cytokine production revealed by IL-4 dual-reporter mice.

Immunity ·Vol. 23 ·No. 4 ·2005-10-00 ·Pages 419-29

Mohrs K, Wakil AE, Killeen N, Locksley RM, Mohrs M

Abstract

To monitor IL-4 expression at the single-cell level, we generated mice with insertions of different reporter genes into both copies of the Il4 gene that permitted the simultaneous analysis of IL-4 transcripts via GFP and IL-4 protein secretion by use of huCD2. Innate and adaptive cells competent for IL-4 production were marked by GFP, while cells that presently or recently secreted IL-4 additionally displayed huCD2. After challenge with the strictly enteric helminth, Heligmosomoides polygyrus, GFP-positive innate and adaptive cells disseminated widely, but IL-4 secretion was predominantly mediated by CD4+ T cells in the intestines and draining lymphoid organs. IL-4-competent cells persisted in cured animals, and memory responses reflected rapid cytokine production at the site of rechallenge. These data reveal a two-step process for cytokine production: the first generating poised cells that disseminate systemically and the second inducing the rapid production of the cytokine in response to local stimulation.

MeSH Terms
Animals Antigens, Helminth CD2 Antigens/metabolism Cytokines/biosynthesis Genes, Reporter Green Fluorescent Proteins/genetics,immunology Interleukin-4/genetics,immunology,metabolism Lymphocytes/immunology Mice Mice, Transgenic Nematospiroides dubius/immunology T-Lymphocytes/immunology
Chemicals
Antigens, Helminth CD2 Antigens Cytokines Green Fluorescent Proteins Interleukin-4
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Mohrs Katja
Trudeau Institute, Saranac Lake, New York 12983, USA.
Wakil Adil E
Killeen Nigel
Locksley Richard M
Mohrs Markus
References (52)
52 references, click to expand
  1. Differences between IL-4- and IL-4 receptor alpha-deficient mice in chronic leishmaniasis reveal a protective role for IL-13 receptor signaling.
    J Immunol. 1999 Jun 15;162(12):7302-8 PMID: 10358179
  2. Immunologic basis of antigen-induced airway hyperresponsiveness.
    Annu Rev Immunol. 1999;17:255-81 PMID: 10358759
  3. T cells undergo rapid ON/OFF but not ON/OFF/ON cycling of cytokine production in response to antigen.
    J Immunol. 2005 Jan 15;174(2):718-26 PMID: 15634891
  4. Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production.
    J Immunol. 2005 Jan 15;174(2):1063-72 PMID: 15634931
  5. CD8- dendritic cell activation status plays an integral role in influencing Th2 response development.
    J Immunol. 2001 Aug 15;167(4):1982-8 PMID: 11489979
  6. Preferential localization of effector memory cells in nonlymphoid tissue.
    Science. 2001 Mar 23;291(5512):2413-7 PMID: 11264538
  7. CD27 is required for generation and long-term maintenance of T cell immunity.
    Nat Immunol. 2000 Nov;1(5):433-40 PMID: 11062504
  8. Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets.
    Immunity. 2001 Mar;14(3):205-15 PMID: 11290331
  9. IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils.
    Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13962-6 PMID: 10570181
  10. Stat6 regulation of in vivo IL-4 responses.
    J Immunol. 2000 Mar 1;164(5):2303-10 PMID: 10679064
  11. Regulation of expression of IL-4 alleles: analysis using a chimeric GFP/IL-4 gene.
    Immunity. 2001 Jan;14(1):1-11 PMID: 11163225
  12. Visualizing the generation of memory CD4 T cells in the whole body.
    Nature. 2001 Mar 1;410(6824):101-5 PMID: 11242050
  13. Analysis of type 2 immunity in vivo with a bicistronic IL-4 reporter.
    Immunity. 2001 Aug;15(2):303-11 PMID: 11520464
  14. Deletion of a coordinate regulator of type 2 cytokine expression in mice.
    Nat Immunol. 2001 Sep;2(9):842-7 PMID: 11526400
  15. Regulation of internal ribosomal entry site-mediated translation by phosphorylation of the translation initiation factor eIF2alpha.
    J Biol Chem. 2002 May 24;277(21):19198-205 PMID: 11877448
  16. Helper T cells regulate type-2 innate immunity in vivo.
    Nature. 2002 Dec 19-26;420(6917):825-9 PMID: 12490951
  17. Stat signals release activated naive Th cells from an anergic checkpoint.
    J Immunol. 2003 Feb 15;170(4):1870-6 PMID: 12574353
  18. Preferential accumulation of antigen-specific effector CD4 T cells at an antigen injection site involves CD62E-dependent migration but not local proliferation.
    J Exp Med. 2003 Mar 17;197(6):751-62 PMID: 12629067
  19. The immune response to parasitic helminths: insights from murine models.
    Trends Immunol. 2003 May;24(5):269-77 PMID: 12738422
  20. An epigenetic view of helper T cell differentiation.
    Nat Immunol. 2003 Jul;4(7):616-23 PMID: 12830136
  21. Regulation of the Th2 cytokine locus by a locus control region.
    Immunity. 2003 Jul;19(1):145-53 PMID: 12871646
  22. Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function.
    J Exp Med. 2003 Oct 6;198(7):1069-76 PMID: 14530376
  23. Basal chromatin modification at the IL-4 gene in helper T cells.
    J Immunol. 2003 Dec 15;171(12):6672-9 PMID: 14662870
  24. Peripheral CD4 T cells rapidly accumulate at the host: parasite interface during an inflammatory Th2 memory response.
    J Immunol. 2004 Feb 15;172(4):2424-30 PMID: 14764713
  25. Probabilistic regulation of IL-4 production in Th2 cells: accessibility at the Il4 locus.
    Immunity. 2004 Feb;20(2):193-203 PMID: 14975241
  26. Type 2 immunity reflects orchestrated recruitment of cells committed to IL-4 production.
    Immunity. 2004 Mar;20(3):267-77 PMID: 15030771
  27. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite.
    J Exp Med. 2004 Aug 16;200(4):507-17 PMID: 15314076
  28. Basophils initiate IL-4 production during a memory T-dependent response.
    J Exp Med. 2004 Oct 4;200(7):857-70 PMID: 15466620
  29. Vaccination against Nematospiroides dubius in mice using adult worm extracts as antigens.
    Aust J Exp Biol Med Sci. 1985 Aug;63 ( Pt 4):423-30 PMID: 4084141
  30. Immunological relationships during primary infection with Heligmosomoides polygyrus (Nematospiroides dubius): dose-dependent expulsion of adult worms.
    Parasitology. 1989 Feb;98 ( Pt 1):115-24 PMID: 2717211
  31. Mouse splenic and bone marrow cell populations that express high-affinity Fc epsilon receptors and produce interleukin 4 are highly enriched in basophils.
    Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2835-9 PMID: 1826367
  32. Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice.
    Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5513-7 PMID: 2062833
  33. Heligmosomoides polygyrus: CD4+ but not CD8+ T cells regulate the IgE response and protective immunity in mice.
    Exp Parasitol. 1991 Nov;73(4):500-11 PMID: 1683629
  34. A primary intestinal helminthic infection rapidly induces a gut-associated elevation of Th2-associated cytokines and IL-3.
    J Immunol. 1993 Apr 15;150(8 Pt 1):3434-41 PMID: 8468481
  35. Abolition of anaphylaxis by targeted disruption of the high affinity immunoglobulin E receptor alpha chain gene.
    Cell. 1993 Dec 3;75(5):969-76 PMID: 8252632
  36. Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo.
    J Immunol. 1994 Apr 1;152(7):3282-93 PMID: 7511642
  37. CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3.
    J Exp Med. 1994 Apr 1;179(4):1285-95 PMID: 7908323
  38. A lineage-specific transcriptional silencer regulates CD4 gene expression during T lymphocyte development.
    Cell. 1994 Jun 17;77(6):917-29 PMID: 8004678
  39. Entry of naive CD4 T cells into peripheral lymph nodes requires L-selectin.
    J Exp Med. 1994 Dec 1;180(6):2401-6 PMID: 7525854
  40. The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo.
    Immunity. 1994 Dec;1(9):741-9 PMID: 7895163
  41. Functional diversity of helper T lymphocytes.
    Nature. 1996 Oct 31;383(6603):787-93 PMID: 8893001
  42. Age-dependent intestinal lymphoproliferative disorder due to stem cell factor receptor deficiency: parameters in small and large intestine.
    J Immunol. 1997 Feb 1;158(3):1417-27 PMID: 9013987
  43. IgE enhances mouse mast cell Fc(epsilon)RI expression in vitro and in vivo: evidence for a novel amplification mechanism in IgE-dependent reactions.
    J Exp Med. 1997 Feb 17;185(4):663-72 PMID: 9034145
  44. Functions of IL-4 and control of its expression.
    Crit Rev Immunol. 1997;17(1):1-32 PMID: 9034722
  45. Cytokine regulation of host defense against parasitic gastrointestinal nematodes: lessons from studies with rodent models.
    Annu Rev Immunol. 1997;15:505-33 PMID: 9143698
  46. Starting at the beginning, middle, and end: translation initiation in eukaryotes.
    Cell. 1997 Jun 13;89(6):831-8 PMID: 9200601
  47. Requirement for CD44 in activated T cell extravasation into an inflammatory site.
    Science. 1997 Oct 24;278(5338):672-5 PMID: 9381175
  48. Negative regulation of T cell homing by CD43.
    Immunity. 1998 Mar;8(3):373-81 PMID: 9529154
  49. Independent and epigenetic regulation of the interleukin-4 alleles in CD4+ T cells.
    Science. 1998 Aug 28;281(5381):1352-4 PMID: 9721100
  50. Regulation of IL-4 expression by activation of individual alleles.
    Immunity. 1998 Aug;9(2):217-28 PMID: 9729042
  51. Marking IL-4-producing cells by knock-in of the IL-4 gene.
    Int Immunol. 1999 Feb;11(2):243-7 PMID: 10069422
  52. Deletion of a conserved Il4 silencer impairs T helper type 1-mediated immunity.
    Nat Immunol. 2004 Dec;5(12):1251-9 PMID: 15516924
Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1074-7613
DOI
10.1016/j.immuni.2005.09.006
Published
2005-10-00
Pages
419-29
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC2826320
Subset
IM
Grants
NIAID NIH HHS · AI45666 · United States
NIAID NIH HHS · P01 AI046530 · United States
NIAID NIH HHS · AI046530 · United States
NIAID NIH HHS · R01 AI026918 · United States
NIAID NIH HHS · P01 AI045666 · United States
NIAID NIH HHS · R01 AI030663-15 · United States
NIAID NIH HHS · R01 AI030663 · United States
External Links
PubMed source DOI: 10.1016/j.immuni.2005.09.006 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2