This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Okahashi, N. Articles by McGhee, J. R. Search for Related Content PubMed PubMed Citation Articles by Okahashi, N. Articles by McGhee, J. R.

 Previous Article  |  Next Article 

Infect. Immun., 05 1996, 1516-1525, Vol 64, No. 5
Copyright © 1996, American Society for Microbiology

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

N Okahashi, M Yamamoto, JL Vancott, SN Chatfield, M Roberts, H Bluethmann, T Hiroi, H Kiyono and JR McGhee
Mucosal Immunization Research Group, University of Alabama, Birmingham Medical Center 35294, USA.

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.

This article has been cited by other articles:

• Ochoa-Reparaz, J., Rynda, A., Ascon, M. A., Yang, X., Kochetkova, I., Riccardi, C., Callis, G., Trunkle, T., Pascual, D. W. (2008). IL-13 Production by Regulatory T Cells Protects against Experimental Autoimmune Encephalomyelitis Independently of Autoantigen. J. Immunol. 181: 954-968 [Abstract] [Full Text]  
• Schnitzler, A. C., Burke, J. M., Wetzler, L. M. (2007). Induction of Cell Signaling Events by the Cholera Toxin B Subunit in Antigen-Presenting Cells. Infect. Immun. 75: 3150-3159 [Abstract] [Full Text]  
• Kataoka, K., Fujihashi, K., Sekine, S., Fukuiwa, T., Kobayashi, R., Suzuki, H., Nagata, H., Takatsu, K., Shizukuishi, S., McGhee, J. R., Fujihashi, K. (2007). Nasal Cholera Toxin Elicits IL-5 and IL-5 Receptor {alpha}-Chain Expressing B-1a B Cells for Innate Mucosal IgA Antibody Responses. J. Immunol. 178: 6058-6065 [Abstract] [Full Text]  
• Duverger, A., Jackson, R. J., van Ginkel, F. W., Fischer, R., Tafaro, A., Leppla, S. H., Fujihashi, K., Kiyono, H., McGhee, J. R., Boyaka, P. N. (2006). Bacillus anthracis Edema Toxin Acts as an Adjuvant for Mucosal Immune Responses to Nasally Administered Vaccine Antigens. J. Immunol. 176: 1776-1783 [Abstract] [Full Text]  
• Jun, S., Gilmore, W., Callis, G., Rynda, A., Haddad, A., Pascual, D. W. (2005). A Live Diarrheal Vaccine Imprints a Th2 Cell Bias and Acts as an Anti-Inflammatory Vaccine. J. Immunol. 175: 6733-6740 [Abstract] [Full Text]  
• Ascon, M. A., Ochoa-Reparaz, J., Walters, N., Pascual, D. W. (2005). Partially Assembled K99 Fimbriae Are Required for Protection. Infect. Immun. 73: 7274-7280 [Abstract] [Full Text]  
• Walters, N., Trunkle, T., Sura, M., Pascual, D. W. (2005). Enhanced Immunoglobulin A Response and Protection against Salmonella enterica Serovar Typhimurium in the Absence of the Substance P Receptor. Infect. Immun. 73: 317-324 [Abstract] [Full Text]  
• Yoshino, N., Lu, F. X.-S., Fujihashi, K., Hagiwara, Y., Kataoka, K., Lu, D., Hirst, L., Honda, M., van Ginkel, F. W., Takeda, Y., Miller, C. J., Kiyono, H., McGhee, J. R. (2004). A Novel Adjuvant for Mucosal Immunity to HIV-1 gp120 in Nonhuman Primates. J. Immunol. 173: 6850-6857 [Abstract] [Full Text]  
• Yamamoto, M., Kweon, M.-N., Rennert, P. D., Hiroi, T., Fujihashi, K., McGhee, J. R., Kiyono, H. (2004). Role of Gut-Associated Lymphoreticular Tissues in Antigen-Specific Intestinal IgA Immunity. J. Immunol. 173: 762-769 [Abstract] [Full Text]  
• Woolard, M. D., Hodge, L. M., Jones, H. P., Schoeb, T. R., Simecka, J. W. (2004). The Upper and Lower Respiratory Tracts Differ in Their Requirement of IFN-{gamma} and IL-4 in Controlling Respiratory Mycoplasma Infection and Disease. J. Immunol. 172: 6875-6883 [Abstract] [Full Text]  
• Castagliuolo, I., Sardina, M., Brun, P., DeRos, C., Mastrotto, C., Lovato, L., Palu, G. (2004). Clostridium difficile Toxin A Carboxyl-Terminus Peptide Lacking ADP-Ribosyltransferase Activity Acts as a Mucosal Adjuvant. Infect. Immun. 72: 2827-2836 [Abstract] [Full Text]  
• Tsuji, N., Suzuki, K., Kasuga-Aoki, H., Isobe, T., Arakawa, T., Matsumoto, Y. (2003). Mice Intranasally Immunized with a Recombinant 16-Kilodalton Antigen from Roundworm Ascaris Parasites Are Protected against Larval Migration of Ascaris suum. Infect. Immun. 71: 5314-5323 [Abstract] [Full Text]  
• Lavelle, E. C., McNeela, E., Armstrong, M. E., Leavy, O., Higgins, S. C., Mills, K. H. G. (2003). Cholera Toxin Promotes the Induction of Regulatory T Cells Specific for Bystander Antigens by Modulating Dendritic Cell Activation. J. Immunol. 171: 2384-2392 [Abstract] [Full Text]  
• Garhart, C. A., Nedrud, J. G., Heinzel, F. P., Sigmund, N. E., Czinn, S. J. (2003). Vaccine-Induced Protection against Helicobacter pylori in Mice Lacking Both Antibodies and Interleukin-4. Infect. Immun. 71: 3628-3633 [Abstract] [Full Text]  
• Boyaka, P. N., Tafaro, A., Fischer, R., Leppla, S. H., Fujihashi, K., McGhee, J. R. (2003). Effective Mucosal Immunity to Anthrax: Neutralizing Antibodies and Th Cell Responses Following Nasal Immunization with Protective Antigen. J. Immunol. 170: 5636-5643 [Abstract] [Full Text]  
• Boyaka, P. N., Ohmura, M., Fujihashi, K., Koga, T., Yamamoto, M., Kweon, M.-N., Takeda, Y., Jackson, R. J., Kiyono, H., Yuki, Y., McGhee, J. R. (2003). Chimeras of Labile Toxin One and Cholera Toxin Retain Mucosal Adjuvanticity and Direct Th Cell Subsets Via Their B Subunit. J. Immunol. 170: 454-462 [Abstract] [Full Text]  
• Hoft, D. F., Eickhoff, C. S. (2002). Type 1 Immunity Provides Optimal Protection against Both Mucosal and Systemic Trypanosoma cruzi Challenges. Infect. Immun. 70: 6715-6725 [Abstract] [Full Text]  
• Yang, Q.-B., Martin, M., Michalek, S. M., Katz, J. (2002). Mechanisms of Monophosphoryl Lipid A Augmentation of Host Responses to Recombinant HagB from Porphyromonas gingivalis. Infect. Immun. 70: 3557-3565 [Abstract] [Full Text]  
• Kang, H. Y., Srinivasan, J., Curtiss, R. III (2002). Immune Responses to Recombinant Pneumococcal PspA Antigen Delivered by Live Attenuated Salmonella enterica Serovar Typhimurium Vaccine. Infect. Immun. 70: 1739-1749 [Abstract] [Full Text]  
• Pascual, D. W., White, M. D., Larson, T., Walters, N. (2001). Impaired Mucosal Immunity in L-Selectin-Deficient Mice Orally Immunized with a Salmonella Vaccine Vector. J. Immunol. 167: 407-415 [Abstract] [Full Text]  
• Boyaka, P. N., Marinaro, M., Jackson, R. J., van Ginkel, F. W., Cormet-Boyaka, E., Kirk, K. L., Kensil, C. R., McGhee, J. R. (2001). Oral QS-21 Requires Early IL-4 Help for Induction of Mucosal and Systemic Immunity. J. Immunol. 166: 2283-2290 [Abstract] [Full Text]  
• Aebischer, T., Laforsch, S., Hurwitz, R., Brombacher, F., Meyer, T. F. (2001). Immunity against Helicobacter pylori: Significance of Interleukin-4 Receptor {alpha} Chain Status and Gender of Infected Mice. Infect. Immun. 69: 556-558 [Abstract] [Full Text]  
• Koga, T., McGhee, J. R., Kato, H., Kato, R., Kiyono, H., Fujihashi, K. (2000). Evidence For Early Aging in the Mucosal Immune System. J. Immunol. 165: 5352-5359 [Abstract] [Full Text]  
• Yamamoto, M., Rennert, P., McGhee, J. R., Kweon, M.-N., Yamamoto, S., Dohi, T., Otake, S., Bluethmann, H., Fujihashi, K., Kiyono, H. (2000). Alternate Mucosal Immune System: Organized Peyer's Patches Are Not Required for IgA Responses in the Gastrointestinal Tract. J. Immunol. 164: 5184-5191 [Abstract] [Full Text]  
• Simecka, J. W., Jackson, R. J., Kiyono, H., McGhee, J. R. (2000). Mucosally Induced Immunoglobulin E-Associated Inflammation in the Respiratory Tract. Infect. Immun. 68: 672-679 [Abstract] [Full Text]  
• Pascual, D. W., Hone, D. M., Hall, S., van Ginkel, F. W., Yamamoto, M., Walters, N., Fujihashi, K., Powell, R. J., Wu, S., Vancott, J. L., Kiyono, H., McGhee, J. R. (1999). Expression of Recombinant Enterotoxigenic Escherichia coli Colonization Factor Antigen I by Salmonella typhimurium Elicits a Biphasic T Helper Cell Response. Infect. Immun. 67: 6249-6256 [Abstract] [Full Text]  
• Katz, J., Black, K. P., Michalek, S. M. (1999). Host Responses to Recombinant Hemagglutinin B of Porphyromonas gingivalis in an Experimental Rat Model. Infect. Immun. 67: 4352-4359 [Abstract] [Full Text]  
• Yamamoto, M., Kiyono, H., Yamamoto, S., Batanero, E., Kweon, M.-N., Otake, S., Azuma, M., Takeda, Y., McGhee, J. R. (1999). Direct Effects on Antigen-Presenting Cells and T Lymphocytes Explain the Adjuvanticity of a Nontoxic Cholera Toxin Mutant. J. Immunol. 162: 7015-7021 [Abstract] [Full Text]  
• Lillard, J. W. Jr., Boyaka, P. N., Hedrick, J. A., Zlotnik, A., McGhee, J. R. (1999). Lymphotactin Acts as an Innate Mucosal Adjuvant. J. Immunol. 162: 1959-1965 [Abstract] [Full Text]  
• Braun, M. C., He, J., Wu, C.-Y., Kelsall, B. L. (1999). Cholera Toxin Suppresses Interleukin (IL)-12 Production and IL-12 Receptor beta 1 and beta 2 Chain Expression. JEM 189: 541-552 [Abstract] [Full Text]  
• Ascon, M. A., Hone, D. M., Walters, N., Pascual, D. W. (1998). Oral Immunization with a Salmonella typhimurium Vaccine Vector Expressing Recombinant Enterotoxigenic Escherichia coli K99 Fimbriae Elicits Elevated Antibody Titers for Protective Immunity. Infect. Immun. 66: 5470-5476 [Abstract] [Full Text]  
• Itoh, M., Ishihara, K., Hiroi, T., Ok Lee, B., Maeda, H., Iijima, H., Yanagita, M., Kiyono, H., Hirano, T. (1998). Deletion of Bone Marrow Stromal Cell Antigen-1 (CD157) Gene Impaired Systemic Thymus Independent-2 Antigen-Induced IgG3 and Mucosal TD Antigen-Elicited IgA Responses. J. Immunol. 161: 3974-3983 [Abstract] [Full Text]  
• Yamamoto, M., Briles, D. E., Yamamoto, S., Ohmura, M., Kiyono, H., McGhee, J. R. (1998). A Nontoxic Adjuvant for Mucosal Immunity to Pneumococcal Surface Protein A. J. Immunol. 161: 4115-4121 [Abstract] [Full Text]  
• Kweon, M.-N., Fujihashi, K., VanCott, J. L., Higuchi, K., Yamamoto, M., McGhee, J. R., Kiyono, H. (1998). Lack of Orally Induced Systemic Unresponsiveness in IFN-{gamma} Knockout Mice. J. Immunol. 160: 1687-1693 [Abstract] [Full Text]  
• Sasaki, S., Hamajima, K., Fukushima, J., Ihata, A., Ishii, N., Gorai, I., Hirahara, F., Mohri, H., Okuda, K. (1998). Comparison of Intranasal and Intramuscular Immunization against Human Immunodeficiency Virus Type 1 with a DNA-Monophosphoryl Lipid A Adjuvant Vaccine. Infect. Immun. 66: 823-826 [Abstract] [Full Text]  
• Yamamoto, S., Kiyono, H., Yamamoto, M., Imaoka, K., Yamamoto, M., Fujihashi, K., Van Ginkel, F. W., Noda, M., Takeda, Y., McGhee, J. R. (1997). A nontoxic mutant of cholera toxin elicits Th2-type responses for enhanced mucosal immunity. Proc. Natl. Acad. Sci. USA 94: 5267-5272 [Abstract] [Full Text]  
• Marinaro, M., Boyaka, P. N., Finkelman, F. D., Kiyono, H., Jackson, R. J., Jirillo, E., McGhee, J. R. (1997). Oral but Not Parenteral Interleukin (IL)-12 Redirects T Helper 2 (Th2)-type Responses to an Oral Vaccine Without Altering Mucosal IgA Responses. JEM 185: 415-428 [Abstract] [Full Text]