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. 1996 May 1;183(5):2129–2142. doi: 10.1084/jem.183.5.2129

CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response

PMCID: PMC2192549  PMID: 8642323

Abstract

The ligand for CD40 (CD40L) is expressed on the surface of activated CD4+ T cells and its role in T-B cell collaborations and thymus- dependent humoral immunity is well established. Recently, by generating CD40L-knockout mice, we have confirmed its previously described role in humoral immunity and defined another important function of this molecule in the in vivo clonal expansion of antigen-specific CD4+ T cells. Here, we investigated the potential in vivo role of CD40L in antiviral immunity by examining the immune response mounted by CD40L- deficient mice following infection with lymphocytic choriomeningitis virus (LCMV), Pichinde virus, or vesicular stomatitis virus. Humoral immune responses of CD40L-deficient mice to these viruses were severely compromised, although moderate titres of antiviral IgM and some IgG2a were produced by virus-infected CD40L-deficient mice by a CD4+ T cell- independent mechanism. By contrast, CD40L-deficient mice made strong primary CTL responses to all three viruses. Interestingly however, although memory CTL activity was detectable in CD40L-deficient mice two months after infection with LCMV, the memory CTL response was much less efficient than in wild-type mice. Together, the results show that CD40- CD40L interactions are required for strong antiviral humoral immune responses, and reveal a novel role for CD40L in the establishment and/or maintenance of CD8+ CTL memory.

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Selected References

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  1. Ahmed R., Jamieson B. D., Porter D. D. Immune therapy of a persistent and disseminated viral infection. J Virol. 1987 Dec;61(12):3920–3929. doi: 10.1128/jvi.61.12.3920-3929.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ahmed R., Salmi A., Butler L. D., Chiller J. M., Oldstone M. B. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J Exp Med. 1984 Aug 1;160(2):521–540. doi: 10.1084/jem.160.2.521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Armerding D., van Reijsen F. C., Hren A., Mudde G. C. Induction of IgE and IgG1 in human B cell cultures with staphylococcal superantigens: role of helper T cell interaction, resistance to interferon-gamma. Immunobiology. 1993 Jul;188(3):259–273. doi: 10.1016/S0171-2985(11)80234-2. [DOI] [PubMed] [Google Scholar]
  4. Armitage R. J., Fanslow W. C., Strockbine L., Sato T. A., Clifford K. N., Macduff B. M., Anderson D. M., Gimpel S. D., Davis-Smith T., Maliszewski C. R. Molecular and biological characterization of a murine ligand for CD40. Nature. 1992 May 7;357(6373):80–82. doi: 10.1038/357080a0. [DOI] [PubMed] [Google Scholar]
  5. Bachmann M. F., Rohrer U. H., Kündig T. M., Bürki K., Hengartner H., Zinkernagel R. M. The influence of antigen organization on B cell responsiveness. Science. 1993 Nov 26;262(5138):1448–1451. doi: 10.1126/science.8248784. [DOI] [PubMed] [Google Scholar]
  6. Battegay M., Moskophidis D., Rahemtulla A., Hengartner H., Mak T. W., Zinkernagel R. M. Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice. J Virol. 1994 Jul;68(7):4700–4704. doi: 10.1128/jvi.68.7.4700-4704.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Borrow P., Evans C. F., Oldstone M. B. Virus-induced immunosuppression: immune system-mediated destruction of virus-infected dendritic cells results in generalized immune suppression. J Virol. 1995 Feb;69(2):1059–1070. doi: 10.1128/jvi.69.2.1059-1070.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Buchmeier M. J., Oldstone M. B. Protein structure of lymphocytic choriomeningitis virus: evidence for a cell-associated precursor of the virion glycopeptides. Virology. 1979 Nov;99(1):111–120. doi: 10.1016/0042-6822(79)90042-4. [DOI] [PubMed] [Google Scholar]
  9. Buchmeier M. J., Rawls W. E. Variation between strains of hamsters in the lethality of Pichinde virus infections. Infect Immun. 1977 May;16(2):413–421. doi: 10.1128/iai.16.2.413-421.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Burns J. W., Buchmeier M. J. Protein-protein interactions in lymphocytic choriomeningitis virus. Virology. 1991 Aug;183(2):620–629. doi: 10.1016/0042-6822(91)90991-j. [DOI] [PubMed] [Google Scholar]
  11. Byrne J. A., Oldstone M. B. Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus: clearance of virus in vivo. J Virol. 1984 Sep;51(3):682–686. doi: 10.1128/jvi.51.3.682-686.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Charan S., Zinkernagel R. M. Antibody mediated suppression of secondary IgM response in nude mice against vesicular stomatitis virus. J Immunol. 1986 Apr 15;136(8):3057–3061. [PubMed] [Google Scholar]
  13. Cobbold S. P., Jayasuriya A., Nash A., Prospero T. D., Waldmann H. Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature. 1984 Dec 6;312(5994):548–551. doi: 10.1038/312548a0. [DOI] [PubMed] [Google Scholar]
  14. DePolo N. J., Giachetti C., Holland J. J. Continuing coevolution of virus and defective interfering particles and of viral genome sequences during undiluted passages: virus mutants exhibiting nearly complete resistance to formerly dominant defective interfering particles. J Virol. 1987 Feb;61(2):454–464. doi: 10.1128/jvi.61.2.454-464.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Diaz-Sanchez D., Chegini S., Zhang K., Saxon A. CD58 (LFA-3) stimulation provides a signal for human isotype switching and IgE production distinct from CD40. J Immunol. 1994 Jul 1;153(1):10–20. [PubMed] [Google Scholar]
  16. Dutko F. J., Oldstone M. B. Genomic and biological variation among commonly used lymphocytic choriomeningitis virus strains. J Gen Virol. 1983 Aug;64(Pt 8):1689–1698. doi: 10.1099/0022-1317-64-8-1689. [DOI] [PubMed] [Google Scholar]
  17. Foy T. M., Durie F. H., Noelle R. J. The expansive role of CD40 and its ligand, gp39, in immunity. Semin Immunol. 1994 Oct;6(5):259–266. doi: 10.1006/smim.1994.1034. [DOI] [PubMed] [Google Scholar]
  18. Foy T. M., Laman J. D., Ledbetter J. A., Aruffo A., Claassen E., Noelle R. J. gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory. J Exp Med. 1994 Jul 1;180(1):157–163. doi: 10.1084/jem.180.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Foy T. M., Shepherd D. M., Durie F. H., Aruffo A., Ledbetter J. A., Noelle R. J. In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39. J Exp Med. 1993 Nov 1;178(5):1567–1575. doi: 10.1084/jem.178.5.1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Freer G., Burkhart C., Ciernik I., Bachmann M. F., Hengartner H., Zinkernagel R. M. Vesicular stomatitis virus Indiana glycoprotein as a T-cell-dependent and -independent antigen. J Virol. 1994 Jun;68(6):3650–3655. doi: 10.1128/jvi.68.6.3650-3655.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Fung-Leung W. P., Kündig T. M., Zinkernagel R. M., Mak T. W. Immune response against lymphocytic choriomeningitis virus infection in mice without CD8 expression. J Exp Med. 1991 Dec 1;174(6):1425–1429. doi: 10.1084/jem.174.6.1425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Goodman-Snitkoff G., Mannino R. J., McSharry J. J. The glycoprotein isolated from vesicular stomatitis virus is mitogenic for mouse B lymphocytes. J Exp Med. 1981 Jun 1;153(6):1489–1502. doi: 10.1084/jem.153.6.1489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Gray D., Dullforce P., Jainandunsing S. Memory B cell development but not germinal center formation is impaired by in vivo blockade of CD40-CD40 ligand interaction. J Exp Med. 1994 Jul 1;180(1):141–155. doi: 10.1084/jem.180.1.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gresser I., Tovey M. G., Maury C., Bandu M. T. Role of interferon in the pathogenesis of virus diseases in mice as demonstrated by the use of anti-interferon serum. II. Studies with herpes simplex, Moloney sarcoma, vesicular stomatitis, Newcastle disease, and influenza viruses. J Exp Med. 1976 Nov 2;144(5):1316–1323. doi: 10.1084/jem.144.5.1316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Grewal I. S., Xu J., Flavell R. A. Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. Nature. 1995 Dec 7;378(6557):617–620. doi: 10.1038/378617a0. [DOI] [PubMed] [Google Scholar]
  26. Hollenbaugh D., Grosmaire L. S., Kullas C. D., Chalupny N. J., Braesch-Andersen S., Noelle R. J., Stamenkovic I., Ledbetter J. A., Aruffo A. The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity. EMBO J. 1992 Dec;11(12):4313–4321. doi: 10.1002/j.1460-2075.1992.tb05530.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hou S., Hyland L., Ryan K. W., Portner A., Doherty P. C. Virus-specific CD8+ T-cell memory determined by clonal burst size. Nature. 1994 Jun 23;369(6482):652–654. doi: 10.1038/369652a0. [DOI] [PubMed] [Google Scholar]
  28. Kasaian M. T., Leite-Morris K. A., Biron C. A. The role of CD4+ cells in sustaining lymphocyte proliferation during lymphocytic choriomeningitis virus infection. J Immunol. 1991 Mar 15;146(6):1955–1963. [PubMed] [Google Scholar]
  29. Lane P., Traunecker A., Hubele S., Inui S., Lanzavecchia A., Gray D. Activated human T cells express a ligand for the human B cell-associated antigen CD40 which participates in T cell-dependent activation of B lymphocytes. Eur J Immunol. 1992 Oct;22(10):2573–2578. doi: 10.1002/eji.1830221016. [DOI] [PubMed] [Google Scholar]
  30. Lau L. L., Jamieson B. D., Somasundaram T., Ahmed R. Cytotoxic T-cell memory without antigen. Nature. 1994 Jun 23;369(6482):648–652. doi: 10.1038/369648a0. [DOI] [PubMed] [Google Scholar]
  31. Lederman S., Yellin M. J., Inghirami G., Lee J. J., Knowles D. M., Chess L. Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help. J Immunol. 1992 Dec 15;149(12):3817–3826. [PubMed] [Google Scholar]
  32. Lefrancios L., Lyles D. S. The interactionof antiody with the major surface glycoprotein of vesicular stomatitis virus. I. Analysis of neutralizing epitopes with monoclonal antibodies. Virology. 1982 Aug;121(1):157–167. [PubMed] [Google Scholar]
  33. Lefrancois L. Protection against lethal viral infection by neutralizing and nonneutralizing monoclonal antibodies: distinct mechanisms of action in vivo. J Virol. 1984 Jul;51(1):208–214. doi: 10.1128/jvi.51.1.208-214.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Leist T. P., Cobbold S. P., Waldmann H., Aguet M., Zinkernagel R. M. Functional analysis of T lymphocyte subsets in antiviral host defense. J Immunol. 1987 Apr 1;138(7):2278–2281. [PubMed] [Google Scholar]
  35. Life P., Gauchat J. F., Schnuriger V., Estoppey S., Mazzei G., Durandy A., Fischer A., Bonnefoy J. Y. T cell clones from an X-linked hyper-immunoglobulin (IgM) patient induce IgE synthesis in vitro despite expression of nonfunctional CD40 ligand. J Exp Med. 1994 Nov 1;180(5):1775–1784. doi: 10.1084/jem.180.5.1775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Liu Y. J., Joshua D. E., Williams G. T., Smith C. A., Gordon J., MacLennan I. C. Mechanism of antigen-driven selection in germinal centres. Nature. 1989 Dec 21;342(6252):929–931. doi: 10.1038/342929a0. [DOI] [PubMed] [Google Scholar]
  37. MacLennan I. C., Gray D. Antigen-driven selection of virgin and memory B cells. Immunol Rev. 1986 Jun;91:61–85. doi: 10.1111/j.1600-065x.1986.tb01484.x. [DOI] [PubMed] [Google Scholar]
  38. Macchia D., Almerigogna F., Parronchi P., Ravina A., Maggi E., Romagnani S. Membrane tumour necrosis factor-alpha is involved in the polyclonal B-cell activation induced by HIV-infected human T cells. Nature. 1993 Jun 3;363(6428):464–466. doi: 10.1038/363464a0. [DOI] [PubMed] [Google Scholar]
  39. Miyoshi K., Harter D. H., Hsu K. C. Neuropathological and immunofluorescence studies of experimental vesicular stomatitis virus encephalitis in mice. J Neuropathol Exp Neurol. 1971 Apr;30(2):266–277. doi: 10.1097/00005072-197104000-00008. [DOI] [PubMed] [Google Scholar]
  40. Mond J. J., Lees A., Snapper C. M. T cell-independent antigens type 2. Annu Rev Immunol. 1995;13:655–692. doi: 10.1146/annurev.iy.13.040195.003255. [DOI] [PubMed] [Google Scholar]
  41. Moskophidis D., Cobbold S. P., Waldmann H., Lehmann-Grube F. Mechanism of recovery from acute virus infection: treatment of lymphocytic choriomeningitis virus-infected mice with monoclonal antibodies reveals that Lyt-2+ T lymphocytes mediate clearance of virus and regulate the antiviral antibody response. J Virol. 1987 Jun;61(6):1867–1874. doi: 10.1128/jvi.61.6.1867-1874.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Müller U., Steinhoff U., Reis L. F., Hemmi S., Pavlovic J., Zinkernagel R. M., Aguet M. Functional role of type I and type II interferons in antiviral defense. Science. 1994 Jun 24;264(5167):1918–1921. doi: 10.1126/science.8009221. [DOI] [PubMed] [Google Scholar]
  43. Noelle R. J., Roy M., Shepherd D. M., Stamenkovic I., Ledbetter J. A., Aruffo A. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6550–6554. doi: 10.1073/pnas.89.14.6550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Notarangelo L. D., Duse M., Ugazio A. G. Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev. 1992;3(2):101–121. [PubMed] [Google Scholar]
  45. Renshaw B. R., Fanslow W. C., 3rd, Armitage R. J., Campbell K. A., Liggitt D., Wright B., Davison B. L., Maliszewski C. R. Humoral immune responses in CD40 ligand-deficient mice. J Exp Med. 1994 Nov 1;180(5):1889–1900. doi: 10.1084/jem.180.5.1889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Roy M., Waldschmidt T., Aruffo A., Ledbetter J. A., Noelle R. J. The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. J Immunol. 1993 Sep 1;151(5):2497–2510. [PubMed] [Google Scholar]
  47. Schreiber R. D., Hicks L. J., Celada A., Buchmeier N. A., Gray P. W. Monoclonal antibodies to murine gamma-interferon which differentially modulate macrophage activation and antiviral activity. J Immunol. 1985 Mar;134(3):1609–1618. [PubMed] [Google Scholar]
  48. Slifka M. K., Matloubian M., Ahmed R. Bone marrow is a major site of long-term antibody production after acute viral infection. J Virol. 1995 Mar;69(3):1895–1902. doi: 10.1128/jvi.69.3.1895-1902.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Spriggs M. K., Armitage R. J., Strockbine L., Clifford K. N., Macduff B. M., Sato T. A., Maliszewski C. R., Fanslow W. C. Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J Exp Med. 1992 Dec 1;176(6):1543–1550. doi: 10.1084/jem.176.6.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Steinhoff U., Müller U., Schertler A., Hengartner H., Aguet M., Zinkernagel R. M. Antiviral protection by vesicular stomatitis virus-specific antibodies in alpha/beta interferon receptor-deficient mice. J Virol. 1995 Apr;69(4):2153–2158. doi: 10.1128/jvi.69.4.2153-2158.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Tew J. G., DiLosa R. M., Burton G. F., Kosco M. H., Kupp L. I., Masuda A., Szakal A. K. Germinal centers and antibody production in bone marrow. Immunol Rev. 1992 Apr;126:99–112. doi: 10.1111/j.1600-065x.1992.tb00633.x. [DOI] [PubMed] [Google Scholar]
  52. Van Kooten C., Banchereau J. CD40-CD40 ligand: a multifunctional receptor-ligand pair. Adv Immunol. 1996;61:1–77. doi: 10.1016/s0065-2776(08)60865-2. [DOI] [PubMed] [Google Scholar]
  53. Van den Eertwegh A. J., Noelle R. J., Roy M., Shepherd D. M., Aruffo A., Ledbetter J. A., Boersma W. J., Claassen E. In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. I. In vivo expression of CD40 ligand, cytokines, and antibody production delineates sites of cognate T-B cell interactions. J Exp Med. 1993 Nov 1;178(5):1555–1565. doi: 10.1084/jem.178.5.1555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Wang Z., Karras J. G., Howard R. G., Rothstein T. L. Induction of bcl-x by CD40 engagement rescues sIg-induced apoptosis in murine B cells. J Immunol. 1995 Oct 15;155(8):3722–3725. [PubMed] [Google Scholar]
  55. Whitton J. L., Oldstone M. B. Class I MHC can present an endogenous peptide to cytotoxic T lymphocytes. J Exp Med. 1989 Sep 1;170(3):1033–1038. doi: 10.1084/jem.170.3.1033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Whitton J. L., Sheng N., Oldstone M. B., McKee T. A. A "string-of-beads" vaccine, comprising linked minigenes, confers protection from lethal-dose virus challenge. J Virol. 1993 Jan;67(1):348–352. doi: 10.1128/jvi.67.1.348-352.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Whitton J. L., Southern P. J., Oldstone M. B. Analyses of the cytotoxic T lymphocyte responses to glycoprotein and nucleoprotein components of lymphocytic choriomeningitis virus. Virology. 1988 Feb;162(2):321–327. doi: 10.1016/0042-6822(88)90471-0. [DOI] [PubMed] [Google Scholar]
  58. Xu J., Foy T. M., Laman J. D., Elliott E. A., Dunn J. J., Waldschmidt T. J., Elsemore J., Noelle R. J., Flavell R. A. Mice deficient for the CD40 ligand. Immunity. 1994 Aug;1(5):423–431. doi: 10.1016/1074-7613(94)90073-6. [DOI] [PubMed] [Google Scholar]
  59. van den Eertwegh A. J., Laman J. D., Noelle R. J., Boersma W. J., Claassen E. In vivo T-B cell interactions and cytokine-production in the spleen. Semin Immunol. 1994 Oct;6(5):327–336. doi: 10.1006/smim.1994.1041. [DOI] [PubMed] [Google Scholar]
  60. von Herrath M. G., Yokoyama M., Dockter J., Oldstone M. B., Whitton J. L. CD4-deficient mice have reduced levels of memory cytotoxic T lymphocytes after immunization and show diminished resistance to subsequent virus challenge. J Virol. 1996 Feb;70(2):1072–1079. doi: 10.1128/jvi.70.2.1072-1079.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]

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