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. 1996 Dec;70(12):8997–9002. doi: 10.1128/jvi.70.12.8997-9002.1996

T-cell-mediated immunity to lymphocytic choriomeningitis virus in beta2-integrin (CD18)- and ICAM-1 (CD54)-deficient mice.

J P Christensen 1, O Marker 1, A R Thomsen 1
PMCID: PMC190999  PMID: 8971031

Abstract

The T-cell response to lymphocytic choriomeningitis virus was studied in mice with deficient expression of beta2-integrins or ICAM-1. In such mice, the generation of virus-specific cytotoxic T lymphocytes was only slightly impaired and bystander activation was as extensive as that observed in wild-type mice. T-cell-mediated inflammation, assessed as primary footpad swelling and susceptibility to intracerebral infection, was slightly compromised only in beta2-integrin-deficient mice. However, adoptive immunization of mutant mice soon after local infection did reveal a reduced capacity to support the inflammatory reaction, indicating that under conditions of more limited immune activation both molecules do play a role in formation of the inflammatory exudate. Finally, virus control was found to be somewhat impaired in both mutant strains. In conclusion, our results indicate that although LFA-1-ICAM-1 interaction is important for certain aspects of the T-cell-mediated response to viruses, T-cell activation is surprisingly intact in these mutant mice, indicating extensive functional redundancy within cell interaction molecules.

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Selected References

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  1. Allan J. E., Dixon J. E., Doherty P. C. Nature of the inflammatory process in the central nervous system of mice infected with lymphocytic choriomeningitis virus. Curr Top Microbiol Immunol. 1987;134:131–143. doi: 10.1007/978-3-642-71726-0_6. [DOI] [PubMed] [Google Scholar]
  2. Andersen I. H., Marker O., Thomsen A. R. Breakdown of blood-brain barrier function in the murine lymphocytic choriomeningitis virus infection mediated by virus-specific CD8+ T cells. J Neuroimmunol. 1991 Feb;31(2):155–163. doi: 10.1016/0165-5728(91)90021-x. [DOI] [PubMed] [Google Scholar]
  3. Anderson D. C., Schmalsteig F. C., Finegold M. J., Hughes B. J., Rothlein R., Miller L. J., Kohl S., Tosi M. F., Jacobs R. L., Waldrop T. C. The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features. J Infect Dis. 1985 Oct;152(4):668–689. doi: 10.1093/infdis/152.4.668. [DOI] [PubMed] [Google Scholar]
  4. Andersson E. C., Christensen J. P., Marker O., Thomsen A. R. Changes in cell adhesion molecule expression on T cells associated with systemic virus infection. J Immunol. 1994 Feb 1;152(3):1237–1245. [PubMed] [Google Scholar]
  5. Andersson E. C., Christensen J. P., Scheynius A., Marker O., Thomsen A. R. Lymphocytic choriomeningitis virus infection is associated with long-standing perturbation of LFA-1 expression on CD8+ T cells. Scand J Immunol. 1995 Jul;42(1):110–118. doi: 10.1111/j.1365-3083.1995.tb03633.x. [DOI] [PubMed] [Google Scholar]
  6. Arnaout M. A. Leukocyte adhesion molecules deficiency: its structural basis, pathophysiology and implications for modulating the inflammatory response. Immunol Rev. 1990 Apr;114:145–180. doi: 10.1111/j.1600-065x.1990.tb00564.x. [DOI] [PubMed] [Google Scholar]
  7. Arnaout M. A., Spits H., Terhorst C., Pitt J., Todd R. F., 3rd Deficiency of a leukocyte surface glycoprotein (LFA-1) in two patients with Mo1 deficiency. Effects of cell activation on Mo1/LFA-1 surface expression in normal and deficient leukocytes. J Clin Invest. 1984 Oct;74(4):1291–1300. doi: 10.1172/JCI111539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brod S. A., Purvee M., Benjamin D., Hafler D. A. T-T cell interactions are mediated by adhesion molecules. Eur J Immunol. 1990 Oct;20(10):2259–2268. doi: 10.1002/eji.1830201015. [DOI] [PubMed] [Google Scholar]
  9. Cavallo F., Martin-Fontecha A., Bellone M., Heltai S., Gatti E., Tornaghi P., Freschi M., Forni G., Dellabona P., Casorati G. Co-expression of B7-1 and ICAM-1 on tumors is required for rejection and the establishment of a memory response. Eur J Immunol. 1995 May;25(5):1154–1162. doi: 10.1002/eji.1830250504. [DOI] [PubMed] [Google Scholar]
  10. Ceredig R., Allan J. E., Tabi Z., Lynch F., Doherty P. C. Phenotypic analysis of the inflammatory exudate in murine lymphocytic choriomeningitis. J Exp Med. 1987 Jun 1;165(6):1539–1551. doi: 10.1084/jem.165.6.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Christensen J. P., Andersson E. C., Scheynius A., Marker O., Thomsen A. R. Alpha 4 integrin directs virus-activated CD8+ T cells to sites of infection. J Immunol. 1995 May 15;154(10):5293–5301. [PubMed] [Google Scholar]
  12. Christensen J. P., Röpke C., Thomsen A. R. Virus-induced polyclonal T cell activation is followed by apoptosis: partitioning of CD8+ T cells based on alpha 4 integrin expression. Int Immunol. 1996 May;8(5):707–715. doi: 10.1093/intimm/8.5.707. [DOI] [PubMed] [Google Scholar]
  13. Christensen J. P., Stenvang J. P., Marker O., Thomsen A. R. Characterization of virus-primed CD8+ T cells with a type 1 cytokine profile. Int Immunol. 1996 Sep;8(9):1453–1461. doi: 10.1093/intimm/8.9.1453. [DOI] [PubMed] [Google Scholar]
  14. Cousens L. P., Orange J. S., Biron C. A. Endogenous IL-2 contributes to T cell expansion and IFN-gamma production during lymphocytic choriomeningitis virus infection. J Immunol. 1995 Dec 15;155(12):5690–5699. [PubMed] [Google Scholar]
  15. Davignon D., Martz E., Reynolds T., Kürzinger K., Springer T. A. Lymphocyte function-associated antigen 1 (LFA-1): a surface antigen distinct from Lyt-2,3 that participates in T lymphocyte-mediated killing. Proc Natl Acad Sci U S A. 1981 Jul;78(7):4535–4539. doi: 10.1073/pnas.78.7.4535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Diamond M. S., Staunton D. E., de Fougerolles A. R., Stacker S. A., Garcia-Aguilar J., Hibbs M. L., Springer T. A. ICAM-1 (CD54): a counter-receptor for Mac-1 (CD11b/CD18). J Cell Biol. 1990 Dec;111(6 Pt 2):3129–3139. doi: 10.1083/jcb.111.6.3129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Doherty P. C., Allan J. E., Lynch F., Ceredig R. Dissection of an inflammatory process induced by CD8+ T cells. Immunol Today. 1990 Feb;11(2):55–59. doi: 10.1016/0167-5699(90)90019-6. [DOI] [PubMed] [Google Scholar]
  18. Dransfield I., Buckle A. M., Hogg N. Early events of the immune response mediated by leukocyte integrins. Immunol Rev. 1990 Apr;114:29–44. doi: 10.1111/j.1600-065x.1990.tb00560.x. [DOI] [PubMed] [Google Scholar]
  19. Dustin M. L., Rothlein R., Bhan A. K., Dinarello C. A., Springer T. A. Induction by IL 1 and interferon-gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol. 1986 Jul 1;137(1):245–254. [PubMed] [Google Scholar]
  20. Evans C. F., Rall G. F., Killeen N., Littman D., Oldstone M. B. CD2-deficient mice generate virus-specific cytotoxic T lymphocytes upon infection with lymphocytic choriomeningitis virus. J Immunol. 1993 Dec 1;151(11):6259–6264. [PubMed] [Google Scholar]
  21. Griffiths C. E., Voorhees J. J., Nickoloff B. J. Characterization of intercellular adhesion molecule-1 and HLA-DR expression in normal and inflamed skin: modulation by recombinant gamma interferon and tumor necrosis factor. J Am Acad Dermatol. 1989 Apr;20(4):617–629. doi: 10.1016/s0190-9622(89)70073-6. [DOI] [PubMed] [Google Scholar]
  22. Hasegawa Y., Yokono K., Taki T., Amano K., Tominaga Y., Yoneda R., Yagi N., Maeda S., Yagita H., Okumura K. Prevention of autoimmune insulin-dependent diabetes in non-obese diabetic mice by anti-LFA-1 and anti-ICAM-1 mAb. Int Immunol. 1994 Jun;6(6):831–838. doi: 10.1093/intimm/6.6.831. [DOI] [PubMed] [Google Scholar]
  23. Isobe M., Yagita H., Okumura K., Ihara A. Specific acceptance of cardiac allograft after treatment with antibodies to ICAM-1 and LFA-1. Science. 1992 Feb 28;255(5048):1125–1127. doi: 10.1126/science.1347662. [DOI] [PubMed] [Google Scholar]
  24. Issekutz T. B. Lymphocyte homing to sites of inflammation. Curr Opin Immunol. 1992 Jun;4(3):287–293. doi: 10.1016/0952-7915(92)90078-s. [DOI] [PubMed] [Google Scholar]
  25. Kägi D., Ledermann B., Bürki K., Seiler P., Odermatt B., Olsen K. J., Podack E. R., Zinkernagel R. M., Hengartner H. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature. 1994 May 5;369(6475):31–37. doi: 10.1038/369031a0. [DOI] [PubMed] [Google Scholar]
  26. Marker O., Scheynius A., Christensen J. P., Thomsen A. R. Virus-activated T cells regulate expression of adhesion molecules on endothelial cells in sites of infection. J Neuroimmunol. 1995 Oct;62(1):35–42. doi: 10.1016/0165-5728(95)00099-n. [DOI] [PubMed] [Google Scholar]
  27. Marker O., Volkert M. Studies on cell-mediated immunity to lymphocytic choriomeningitis virus in mice. J Exp Med. 1973 Jun 1;137(6):1511–1525. doi: 10.1084/jem.137.6.1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nahill S. R., Welsh R. M. High frequency of cross-reactive cytotoxic T lymphocytes elicited during the virus-induced polyclonal cytotoxic T lymphocyte response. J Exp Med. 1993 Feb 1;177(2):317–327. doi: 10.1084/jem.177.2.317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Neckers L. M., Cossman J. Transferrin receptor induction in mitogen-stimulated human T lymphocytes is required for DNA synthesis and cell division and is regulated by interleukin 2. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3494–3498. doi: 10.1073/pnas.80.11.3494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nielsen H. V., Christensen J. P., Andersson E. C., Marker O., Thomsen A. R. Expression of type 3 complement receptor on activated CD8+ T cells facilitates homing to inflammatory sites. J Immunol. 1994 Sep 1;153(5):2021–2028. [PubMed] [Google Scholar]
  31. Roth M. D. Interleukin 2 induces the expression of CD45RO and the memory phenotype by CD45RA+ peripheral blood lymphocytes. J Exp Med. 1994 Mar 1;179(3):857–864. doi: 10.1084/jem.179.3.857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Scheynius A., Camp R. L., Puré E. Reduced contact sensitivity reactions in mice treated with monoclonal antibodies to leukocyte function-associated molecule-1 and intercellular adhesion molecule-1. J Immunol. 1993 Jan 15;150(2):655–663. [PubMed] [Google Scholar]
  33. Scheynius A., Camp R. L., Puré E. Unresponsiveness to 2,4-dinitro-1-fluoro-benzene after treatment with monoclonal antibodies to leukocyte function-associated molecule-1 and intercellular adhesion molecule-1 during sensitization. J Immunol. 1996 Mar 1;156(5):1804–1809. [PubMed] [Google Scholar]
  34. Selin L. K., Nahill S. R., Welsh R. M. Cross-reactivities in memory cytotoxic T lymphocyte recognition of heterologous viruses. J Exp Med. 1994 Jun 1;179(6):1933–1943. doi: 10.1084/jem.179.6.1933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sharpe A. H. Analysis of lymphocyte costimulation in vivo using transgenic and 'knockout' mice. Curr Opin Immunol. 1995 Jun;7(3):389–395. doi: 10.1016/0952-7915(95)80115-4. [DOI] [PubMed] [Google Scholar]
  36. Shimizu Y., Newman W., Tanaka Y., Shaw S. Lymphocyte interactions with endothelial cells. Immunol Today. 1992 Mar;13(3):106–112. doi: 10.1016/0167-5699(92)90151-V. [DOI] [PubMed] [Google Scholar]
  37. Sligh J. E., Jr, Ballantyne C. M., Rich S. S., Hawkins H. K., Smith C. W., Bradley A., Beaudet A. L. Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8529–8533. doi: 10.1073/pnas.90.18.8529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Springer T. A. Adhesion receptors of the immune system. Nature. 1990 Aug 2;346(6283):425–434. doi: 10.1038/346425a0. [DOI] [PubMed] [Google Scholar]
  39. Starling G. C., McLellan A. D., Egner W., Sorg R. V., Fawcett J., Simmons D. L., Hart D. N. Intercellular adhesion molecule-3 is the predominant co-stimulatory ligand for leukocyte function antigen-1 on human blood dendritic cells. Eur J Immunol. 1995 Sep;25(9):2528–2532. doi: 10.1002/eji.1830250918. [DOI] [PubMed] [Google Scholar]
  40. Thomsen A. R., Marker O. MHC and non-MHC genes regulate elimination of lymphocytic choriomeningitis virus and antiviral cytotoxic T lymphocyte and delayed-type hypersensitivity mediating T lymphocyte activity in parallel. J Immunol. 1989 Feb 15;142(4):1333–1341. [PubMed] [Google Scholar]
  41. Van Seventer G. A., Shimizu Y., Horgan K. J., Shaw S. The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. J Immunol. 1990 Jun 15;144(12):4579–4586. [PubMed] [Google Scholar]
  42. Vyth-Dreese F. A., Dellemijn T. A., Frijhoff A., van Kooyk Y., Figdor C. G. Role of LFA-1/ICAM-1 in interleukin-2-stimulated lymphocyte proliferation. Eur J Immunol. 1993 Dec;23(12):3292–3299. doi: 10.1002/eji.1830231235. [DOI] [PubMed] [Google Scholar]
  43. Wilson R. W., Ballantyne C. M., Smith C. W., Montgomery C., Bradley A., O'Brien W. E., Beaudet A. L. Gene targeting yields a CD18-mutant mouse for study of inflammation. J Immunol. 1993 Aug 1;151(3):1571–1578. [PubMed] [Google Scholar]
  44. Zinkernagel R. M. H-2 restriction of virus-specific T-cell-mediated effector functions in vivo. II. Adoptive transfer of delayed-type hypersensitivity to murine lymphocytic choriomeningits virus is restriced by the K and D region of H-2. J Exp Med. 1976 Sep 1;144(3):776–787. doi: 10.1084/jem.144.3.776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. de Fougerolles A. R., Qin X., Springer T. A. Characterization of the function of intercellular adhesion molecule (ICAM)-3 and comparison with ICAM-1 and ICAM-2 in immune responses. J Exp Med. 1994 Feb 1;179(2):619–629. doi: 10.1084/jem.179.2.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. de Fougerolles A. R., Stacker S. A., Schwarting R., Springer T. A. Characterization of ICAM-2 and evidence for a third counter-receptor for LFA-1. J Exp Med. 1991 Jul 1;174(1):253–267. doi: 10.1084/jem.174.1.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. de Waal Malefyt R., Verma S., Bejarano M. T., Ranes-Goldberg M., Hill M., Spits H. CD2/LFA-3 or LFA-1/ICAM-1 but not CD28/B7 interactions can augment cytotoxicity by virus-specific CD8+ cytotoxic T lymphocytes. Eur J Immunol. 1993 Feb;23(2):418–424. doi: 10.1002/eji.1830230218. [DOI] [PubMed] [Google Scholar]

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