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Infect Immun. May 1996; 64(5): 1516–1525.
PMCID: PMC173956

Oral immunization of interleukin-4 (IL-4) knockout mice with a recombinant Salmonella strain or cholera toxin reveals that CD4+ Th2 cells producing IL-6 and IL-10 are associated with mucosal immunoglobulin A responses.

Abstract

Mucosal immunoglobulin A (IgA) responses are often associated with Th2-type cells and derived cytokines, and interleukin-4 (IL-4) knockout (IL-4-/-) mice with impaired Th2 cells respond poorly to oral antigens. However, we have noted that IL-4-/- mice have normal mucosal IgA levels, which led us to query whether different oral delivery systems could elicit mucosal immunity. Two oral regimens were used: (i) a live recombinant Salmonella strain which expresses fragment C (ToxC) of tetanus toxin, and (ii) soluble tetanus toxoid (TT) with cholera toxin (CT) as an adjuvant. Oral immunization of IL-4-/- mice with recombinant Salmonella vaccine expressing ToxC induced brisk mucosal IgA and serum IgG (mainly IgG2a) anti-TT antibody responses. TT-specific CD4+ T cells from spleen or Peyer's patches produced gamma interferon, indicative of Th1 responses; however, IL-6 and IL-10 were also seen. Oral immunization of IL-4-/- mice with TT and CT induced weak mucosal IgA to TT; however, brisk IgA anti-CT-B responses and CT-B-specific CD4+ T cells producing IL-6 and IL-10 were also noted. These results show that although IL-4-dependent antibody responses are impaired, mucosal IgA responses are induced in IL-4-/- mice. These result suggest that certain cytokines, i.e., IL-6 and IL-10 from Th2-type cells, play an important compensatory role in the induction and regulation of mucosal IgA responses.

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Selected References

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  • Beagley KW, Eldridge JH, Kiyono H, Everson MP, Koopman WJ, Honjo T, McGhee JR. Recombinant murine IL-5 induces high rate IgA synthesis in cycling IgA-positive Peyer's patch B cells. J Immunol. 1988 Sep 15;141(6):2035–2042. [PubMed]
  • Beagley KW, Eldridge JH, Lee F, Kiyono H, Everson MP, Koopman WJ, Hirano T, Kishimoto T, McGhee JR. Interleukins and IgA synthesis. Human and murine interleukin 6 induce high rate IgA secretion in IgA-committed B cells. J Exp Med. 1989 Jun 1;169(6):2133–2148. [PMC free article] [PubMed]
  • Brenner CA, Tam AW, Nelson PA, Engleman EG, Suzuki N, Fry KE, Larrick JW. Message amplification phenotyping (MAPPing): a technique to simultaneously measure multiple mRNAs from small numbers of cells. Biotechniques. 1989 Nov-Dec;7(10):1096–1103. [PubMed]
  • Chatfield SN, Charles IG, Makoff AJ, Oxer MD, Dougan G, Pickard D, Slater D, Fairweather NF. Use of the nirB promoter to direct the stable expression of heterologous antigens in Salmonella oral vaccine strains: development of a single-dose oral tetanus vaccine. Biotechnology (N Y) 1992 Aug;10(8):888–892. [PubMed]
  • Chatfield SN, Strugnell RA, Dougan G. Live Salmonella as vaccines and carriers of foreign antigenic determinants. Vaccine. 1989 Dec;7(6):495–498. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Czerkinsky CC, Nilsson LA, Nygren H, Ouchterlony O, Tarkowski A. A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells. J Immunol Methods. 1983 Dec 16;65(1-2):109–121. [PubMed]
  • deVos T, Dick TA. A rapid method to determine the isotype and specificity of coproantibodies in mice infected with Trichinella or fed cholera toxin. J Immunol Methods. 1991 Aug 9;141(2):285–288. [PubMed]
  • Elson CO, Ealding W. Generalized systemic and mucosal immunity in mice after mucosal stimulation with cholera toxin. J Immunol. 1984 Jun;132(6):2736–2741. [PubMed]
  • Finkelman FD, Holmes J, Katona IM, Urban JF, Jr, Beckmann MP, Park LS, Schooley KA, Coffman RL, Mosmann TR, Paul WE. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol. 1990;8:303–333. [PubMed]
  • Jackson RJ, Fujihashi K, Xu-Amano J, Kiyono H, Elson CO, McGhee JR. Optimizing oral vaccines: induction of systemic and mucosal B-cell and antibody responses to tetanus toxoid by use of cholera toxin as an adjuvant. Infect Immun. 1993 Oct;61(10):4272–4279. [PMC free article] [PubMed]
  • Kagaya K, Watanabe K, Fukazawa Y. Capacity of recombinant gamma interferon to activate macrophages for Salmonella-killing activity. Infect Immun. 1989 Feb;57(2):609–615. [PMC free article] [PubMed]
  • Kiyono H, Bienenstock J, McGhee JR, Ernst PB. The mucosal immune system: features of inductive and effector sites to consider in mucosal immunization and vaccine development. Reg Immunol. 1992 Mar-Apr;4(2):54–62. [PubMed]
  • Kopf M, Le Gros G, Bachmann M, Lamers MC, Bluethmann H, Köhler G. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature. 1993 Mar 18;362(6417):245–248. [PubMed]
  • Kühn R, Rajewsky K, Müller W. Generation and analysis of interleukin-4 deficient mice. Science. 1991 Nov 1;254(5032):707–710. [PubMed]
  • Le Gros G, Ben-Sasson SZ, Seder R, Finkelman FD, Paul WE. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med. 1990 Sep 1;172(3):921–929. [PMC free article] [PubMed]
  • Lu W, Han DS, Yuan J, Andrieu JM. Multi-target PCR analysis by capillary electrophoresis and laser-induced fluorescence. Nature. 1994 Mar 17;368(6468):269–271. [PubMed]
  • Lycke N, Holmgren J. Strong adjuvant properties of cholera toxin on gut mucosal immune responses to orally presented antigens. Immunology. 1986 Oct;59(2):301–308. [PMC free article] [PubMed]
  • Marinaro M, Staats HF, Hiroi T, Jackson RJ, Coste M, Boyaka PN, Okahashi N, Yamamoto M, Kiyono H, Bluethmann H, et al. Mucosal adjuvant effect of cholera toxin in mice results from induction of T helper 2 (Th2) cells and IL-4. J Immunol. 1995 Nov 15;155(10):4621–4629. [PubMed]
  • McGhee JR, Mestecky J, Dertzbaugh MT, Eldridge JH, Hirasawa M, Kiyono H. The mucosal immune system: from fundamental concepts to vaccine development. Vaccine. 1992;10(2):75–88. [PubMed]
  • Mestecky J, McGhee JR. Immunoglobulin A (IgA): molecular and cellular interactions involved in IgA biosynthesis and immune response. Adv Immunol. 1987;40:153–245. [PubMed]
  • Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. [PubMed]
  • Muotiala A, Mäkelä PH. The role of IFN-gamma in murine Salmonella typhimurium infection. Microb Pathog. 1990 Feb;8(2):135–141. [PubMed]
  • Ramarathinam L, Shaban RA, Niesel DW, Klimpel GR. Interferon gamma (IFN-gamma) production by gut-associated lymphoid tissue and spleen following oral Salmonella typhimurium challenge. Microb Pathog. 1991 Nov;11(5):347–356. [PubMed]
  • Ramsay AJ, Husband AJ, Ramshaw IA, Bao S, Matthaei KI, Koehler G, Kopf M. The role of interleukin-6 in mucosal IgA antibody responses in vivo. Science. 1994 Apr 22;264(5158):561–563. [PubMed]
  • Sad S, Mosmann TR. Single IL-2-secreting precursor CD4 T cell can develop into either Th1 or Th2 cytokine secretion phenotype. J Immunol. 1994 Oct 15;153(8):3514–3522. [PubMed]
  • Scott P, Kaufmann SH. The role of T-cell subsets and cytokines in the regulation of infection. Immunol Today. 1991 Oct;12(10):346–348. [PubMed]
  • Sher A, Coffman RL. Regulation of immunity to parasites by T cells and T cell-derived cytokines. Annu Rev Immunol. 1992;10:385–409. [PubMed]
  • Staats HF, Jackson RJ, Marinaro M, Takahashi I, Kiyono H, McGhee JR. Mucosal immunity to infection with implications for vaccine development. Curr Opin Immunol. 1994 Aug;6(4):572–583. [PubMed]
  • Street NE, Mosmann TR. Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J. 1991 Feb;5(2):171–177. [PubMed]
  • Swain SL, Weinberg AD, English M, Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990 Dec 1;145(11):3796–3806. [PubMed]
  • Vajdy M, Kosco-Vilbois MH, Kopf M, Köhler G, Lycke N. Impaired mucosal immune responses in interleukin 4-targeted mice. J Exp Med. 1995 Jan 1;181(1):41–53. [PubMed]
  • VanCott JL, Staats HF, Pascual DW, Roberts M, Chatfield SN, Yamamoto M, Coste M, Carter PB, Kiyono H, McGhee JR. Regulation of mucosal and systemic antibody responses by T helper cell subsets, macrophages, and derived cytokines following oral immunization with live recombinant Salmonella. J Immunol. 1996 Feb 15;156(4):1504–1514. [PubMed]
  • Xu-Amano J, Aicher WK, Taguchi T, Kiyono H, McGhee JR. Selective induction of Th2 cells in murine Peyer's patches by oral immunization. Int Immunol. 1992 Apr;4(4):433–445. [PubMed]
  • Xu-Amano J, Kiyono H, Jackson RJ, Staats HF, Fujihashi K, Burrows PD, Elson CO, Pillai S, McGhee JR. Helper T cell subsets for immunoglobulin A responses: oral immunization with tetanus toxoid and cholera toxin as adjuvant selectively induces Th2 cells in mucosa associated tissues. J Exp Med. 1993 Oct 1;178(4):1309–1320. [PMC free article] [PubMed]

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