• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jvirolPermissionsJournals.ASM.orgJournalJV ArticleJournal InfoAuthorsReviewers
J Virol. Aug 1994; 68(8): 5126–5132.
PMCID: PMC236456

Differential Th1 and Th2 cell responses in male and female BALB/c mice infected with coxsackievirus group B type 3.


Male and female BALB/c mice differ dramatically in susceptibility to myocarditis subsequent to coxsackievirus B3 (CVB3) infection. CVB3 infection of male mice results in substantial inflammatory cell infiltration of the myocardium, and virus-immune lymphocytes from these animals give predominantly a Th1 cell phenotypic response, as determined by predominant immunoglobulin G2a isotypic antibody production and elevated numbers of gamma interferon and interleukin-2 (IL-2)-producing CD4+ T lymphocytes. Females infected with the same virus give predominantly a Th2 cell phenotypic response, as determined by preferential immunoglobulin G1 antibody isotypic responses and increased precursor frequencies of IL-4- and IL-5-producing CD4+ T cells. Treatment of females with testosterone or males with estradiol prior to infection alters subsequent Th subset differentiation, suggesting that the sex-associated hormones have either a direct or indirect effect on CD4+ lymphocyte responses in this model. Treatment of females with 0.1 mg of monoclonal antibody to IL-4 reduces precursor frequencies of IL-4-producing CD4+ T cells and increases frequencies of gamma interferon-producing cells. This treatment also enhances myocardial inflammation, indicating a correlation between Th1-like cell responses and pathogenicity in CVB3 infection. The Th2-like cell may regulate Th1 cell activation. Adoptive transfer of T lymphocytes from CVB3-infected female mice into male animals suppresses the development of myocarditis in the recipients. Treatment of the female donors with monoclonal antibodies to either CD3, CD4, or IL-4 molecules abrogates suppression.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Araneo BA, Dowell T, Diegel M, Daynes RA. Dihydrotestosterone exerts a depressive influence on the production of interleukin-4 (IL-4), IL-5, and gamma-interferon, but not IL-2 by activated murine T cells. Blood. 1991 Aug 1;78(3):688–699. [PubMed]
  • Bhalla AK. Hormones and the immune response. Ann Rheum Dis. 1989 Jan;48(1):1–6. [PMC free article] [PubMed]
  • Bloom BR, Salgame P, Diamond B. Revisiting and revising suppressor T cells. Immunol Today. 1992 Apr;13(4):131–136. [PubMed]
  • Bogen SA, Fogelman I, Abbas AK. Analysis of IL-2, IL-4, and IFN-gamma-producing cells in situ during immune responses to protein antigens. J Immunol. 1993 May 15;150(10):4197–4205. [PubMed]
  • Dalton DK, Pitts-Meek S, Keshav S, Figari IS, Bradley A, Stewart TA. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993 Mar 19;259(5102):1739–1742. [PubMed]
  • Daynes RA, Araneo BA. Contrasting effects of glucocorticoids on the capacity of T cells to produce the growth factors interleukin 2 and interleukin 4. Eur J Immunol. 1989 Dec;19(12):2319–2325. [PubMed]
  • Else KJ, Hültner L, Grencis RK. Modulation of cytokine production and response phenotypes in murine trichuriasis. Parasite Immunol. 1992 Jul;14(4):441–449. [PubMed]
  • Esser C, Radbruch A. Immunoglobulin class switching: molecular and cellular analysis. Annu Rev Immunol. 1990;8:717–735. [PubMed]
  • Falcone V, Marelli P, Zolfino I, Campa M. BCG-activated NK cells regulate the antibody response to SRBC and restore immune reactivity to PPD in BCG-infected mice. Immunol Lett. 1993 Jun;36(3):295–299. [PubMed]
  • Fenoglio JJ, Jr, Ursell PC, Kellogg CF, Drusin RE, Weiss MB. Diagnosis and classification of myocarditis by endomyocardial biopsy. N Engl J Med. 1983 Jan 6;308(1):12–18. [PubMed]
  • Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. [PMC free article] [PubMed]
  • Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991 Dec 1;147(11):3815–3822. [PubMed]
  • Fitch FW, McKisic MD, Lancki DW, Gajewski TF. Differential regulation of murine T lymphocyte subsets. Annu Rev Immunol. 1993;11:29–48. [PubMed]
  • Gajewski TF, Schell SR, Nau G, Fitch FW. Regulation of T-cell activation: differences among T-cell subsets. Immunol Rev. 1989 Oct;111:79–110. [PubMed]
  • Good MF, Boyd AW, Nossal GJ. Analysis of true anti-hapten cytotoxic clones in limit dilution microcultures after correction for "anti-self" activity: precursor frequencies, Ly-2 and Thy-1 phenotype, specificity, and statistical methods. J Immunol. 1983 May;130(5):2046–2055. [PubMed]
  • Grossman CJ. Regulation of the immune system by sex steroids. Endocr Rev. 1984 Summer;5(3):435–455. [PubMed]
  • Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989 Jan 1;169(1):59–72. [PMC free article] [PubMed]
  • Huber SA, Job LP, Auld KR. Influence of sex hormones on Coxsackie B-3 virus infection in Balb/c mice. Cell Immunol. 1982 Feb;67(1):173–179. [PubMed]
  • Huber SA, Job LP, Woodruff JF. Sex-related differences in the pattern of coxsackievirus B-3-induced immune spleen cell cytotoxicity against virus-infected myofibers. Infect Immun. 1981 Apr;32(1):68–73. [PMC free article] [PubMed]
  • Huber SA, Lodge PA. Coxsackievirus B-3 myocarditis in Balb/c mice. Evidence for autoimmunity to myocyte antigens. Am J Pathol. 1984 Jul;116(1):21–29. [PMC free article] [PubMed]
  • Job LP, Lyden DC, Huber SA. Demonstration of suppressor cells in coxsackievirus group B, type 3 infected female Balb/c mice which prevent myocarditis. Cell Immunol. 1986 Mar;98(1):104–113. [PubMed]
  • Kendall C, Ionescu-Matiu I, Dreesman GR. Utilization of the biotin/avidin system to amplify the sensitivity of the enzyme-linked immunosorbent assay (ELISA). J Immunol Methods. 1983 Feb 11;56(3):329–339. [PubMed]
  • Lerner A, Wilson FM, Reyes MP. Enteroviruses and the heart (with special emphasis on the probable role of coxsackieviruses, group B, types 1-5). II. Observations in humans. Mod Concepts Cardiovasc Dis. 1975 Mar;44(3):11–15. [PubMed]
  • Leslie K, Blay R, Haisch C, Lodge A, Weller A, Huber S. Clinical and experimental aspects of viral myocarditis. Clin Microbiol Rev. 1989 Apr;2(2):191–203. [PMC free article] [PubMed]
  • Lyden DC, Olszewski J, Feran M, Job LP, Huber SA. Coxsackievirus B-3-induced myocarditis. Effect of sex steroids on viremia and infectivity of cardiocytes. Am J Pathol. 1987 Mar;126(3):432–438. [PMC free article] [PubMed]
  • Morris L, Troutt AB, Handman E, Kelso A. Changes in the precursor frequencies of IL-4 and IFN-gamma secreting CD4+ cells correlate with resolution of lesions in murine cutaneous leishmaniasis. J Immunol. 1992 Oct 15;149(8):2715–2721. [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]
  • Oswald IP, Gazzinelli RT, Sher A, James SL. IL-10 synergizes with IL-4 and transforming growth factor-beta to inhibit macrophage cytotoxic activity. J Immunol. 1992 Jun 1;148(11):3578–3582. [PubMed]
  • Paavonen T. Hormonal regulation of lymphocyte functions. Med Biol. 1987;65(5-6):229–240. [PubMed]
  • Pearce EJ, Caspar P, Grzych JM, Lewis FA, Sher A. Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med. 1991 Jan 1;173(1):159–166. [PMC free article] [PubMed]
  • Peterson JD, Karpus WJ, Clatch RJ, Miller SD. Split tolerance of Th1 and Th2 cells in tolerance to Theiler's murine encephalomyelitis virus. Eur J Immunol. 1993 Jan;23(1):46–55. [PubMed]
  • Reyes MP, Lerner AM. Coxsackievirus myocarditis--with special reference to acute and chronic effects. Prog Cardiovasc Dis. 1985 May-Jun;27(6):373–394. [PubMed]
  • Röcken M, Saurat JH, Hauser C. A common precursor for CD4+ T cells producing IL-2 or IL-4. J Immunol. 1992 Feb 15;148(4):1031–1036. [PubMed]
  • Romagnani S. Induction of TH1 and TH2 responses: a key role for the 'natural' immune response? Immunol Today. 1992 Oct;13(10):379–381. [PubMed]
  • Romani L, Mencacci A, Cenci E, Spaccapelo R, Mosci P, Puccetti P, Bistoni F. CD4+ subset expression in murine candidiasis. Th responses correlate directly with genetically determined susceptibility or vaccine-induced resistance. J Immunol. 1993 Feb 1;150(3):925–931. [PubMed]
  • Romani L, Mencacci A, Cenci E, Spaccapelo R, Schiaffella E, Tonnetti L, Puccetti P, Bistoni F. Natural killer cells do not play a dominant role in CD4+ subset differentiation in Candida albicans-infected mice. Infect Immun. 1993 Sep;61(9):3769–3774. [PMC free article] [PubMed]
  • Sarvetnick N, Fox HS. Interferon-gamma and the sexual dimorphism of autoimmunity. Mol Biol Med. 1990 Aug;7(4):323–331. [PubMed]
  • Scharton TM, Scott P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J Exp Med. 1993 Aug 1;178(2):567–577. [PMC free article] [PubMed]
  • Steinberg AD, Huston DP, Taurog JD, Cowdery JS, Ravecheé ES. The cellular and genetic basis of murine lupus. Immunol Rev. 1981;55:121–154. [PubMed]
  • Stevenson MM, Tam MF. Differential induction of helper T cell subsets during blood-stage Plasmodium chabaudi AS infection in resistant and susceptible mice. Clin Exp Immunol. 1993 Apr;92(1):77–83. [PMC free article] [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]
  • Styrt B, Sugarman B. Estrogens and infection. Rev Infect Dis. 1991 Nov-Dec;13(6):1139–1150. [PubMed]
  • Thomas JM, Carver FM, Cunningham P, Olsen L, Thomas FT. Veto cells induce long-term kidney allograft tolerance in primates without chronic immunosuppression. Transplant Proc. 1991 Feb;23(1 Pt 1):11–13. [PubMed]
  • Torbett BE, Laxer JA, Glasebrook AL. Frequencies of T cells secreting IL-2 and/or IL-4 among unprimed CD4+ populations. Evidence that clones secreting IL-2 and IL-4 give rise to clones which secrete only IL-4. Immunol Lett. 1990 Jan;23(3):227–233. [PubMed]
  • Varkila K, Chatelain R, Leal LM, Coffman RL. Reconstitution of C.B-17 scid mice with BALB/c T cells initiates a T helper type-1 response and renders them capable of healing Leishmania major infection. Eur J Immunol. 1993 Jan;23(1):262–268. [PubMed]
  • Weaver CT, Hawrylowicz CM, Unanue ER. T helper cell subsets require the expression of distinct costimulatory signals by antigen-presenting cells. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8181–8185. [PMC free article] [PubMed]
  • Weller AH, Simpson K, Herzum M, Van Houten N, Huber SA. Coxsackievirus-B3-induced myocarditis: virus receptor antibodies modulate myocarditis. J Immunol. 1989 Sep 15;143(6):1843–1850. [PubMed]
  • Wong CY, Woodruff JJ, Woodruff JF. Generation of cytotoxic T lymphocytes during coxsackievirus B-3 infection. III. Role of sex. J Immunol. 1977 Aug;119(2):591–597. [PubMed]
  • Woodruff JF. Viral myocarditis. A review. Am J Pathol. 1980 Nov;101(2):425–484. [PMC free article] [PubMed]
  • Woodruff JF, Woodruff JJ. Involvement of T lymphocytes in the pathogenesis of coxsackie virus B3 heart disease. J Immunol. 1974 Dec;113(6):1726–1734. [PubMed]
  • Yamamoto M, Fujihashi K, Beagley KW, McGhee JR, Kiyono H. Cytokine synthesis by intestinal intraepithelial lymphocytes. Both gamma/delta T cell receptor-positive and alpha/beta T cell receptor-positive T cells in the G1 phase of cell cycle produce IFN-gamma and IL-5. J Immunol. 1993 Jan 1;150(1):106–114. [PubMed]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...