Immune Response of β2-Microglobulin-Deficient Mice to Pathogens

  • Jeffrey A. Frelinger
  • Jonathan Serody
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 232)


The ability of hosts to respond to pathogens is one of the driving forces in the selection of the immune system. The immune response to both bacteria and viruses involves the ability of T cell to recognize and to respond to pathogens. Both CD4+ and CD8+ T cells are important in the overall immune response. In the most basic paradigm, CD4+ T cells respond to exogenous antigen, which is internalized, degraded, and presented on the surface of antigen-presenting cells by major histocompatibility complex (MHC)-encoded class II molecules. This arm of the response includes not only helping B cells produce antibodies, but also the production of proinflamatory cytokines, including interferon (INF)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-2. It is often stated that these responses are important in inhibiting the spread of virus from cell to cell by aiding the production of antibodies which neutralize virus and creating a cytokine milieu which does not support virus replication. In contrast, CD8+ T cells respond primarily to peptides derived from endogenously synthesized proteins. The T cells are able to recognize and kill the cells expressing these peptides by at least two major pathways, one utilizing perforin exocytosis and the other utilizing fas-fas ligand interactions. This response has the net effect of removing cells which are producing viruses or other pathogens which have access to the cytoplasm of infected cells. This has given rise to the simple idea that CD4 responses (and antibodies) block virus spread, while CD8 responses remove the source of infection, resulting in clearance of pathogens which hide intracellularly.


Major Histocompatibility Complex Major Histocompatibility Complex Class Mouse Hepatitis Virus Lymphocytic Choriomeningitis Virus Listeria Monocytogenes Infection 
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  1. Asano MS, Ahmed R (1995) Immune conflicts in lymphocytic choriomeningitis virus. Springer Semin Immunopathol 17:247–259PubMedCrossRefGoogle Scholar
  2. Bix M, Liao NS, Zijlstra M, Loring J, Jaenisch R, Raulet D (1991) Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice. Nature 349:329–331PubMedCrossRefGoogle Scholar
  3. Apasov S, Sitkovsky M (1993) Highly lytic CD8+, alpha beta T-cell receptor cytotoxic T cells with major histocompatibility complex (MHC) class I antigen-directed cytotoxicity in beta 2-microglobulin, MHC class I-deficient mice. Proc Natl Acad Sci USA 90:2837–2841PubMedCrossRefGoogle Scholar
  4. Apasov SG, Sitkovsky MV (1994) Development and antigen specificity of CD8+ cytotoxic T lymphocytes in beta 2-microglobulin-negative, MHC class I-deficient mice in response to immunization with tumor cells. J Immunol 152:2087–2097PubMedGoogle Scholar
  5. Barkon ML, Haller BL, Virgin HWT (1996) Circulating immunoglobulin G can play a critical role in clearance of intestinal reovirus infection. J Virol 70:1109–1116PubMedGoogle Scholar
  6. Bender BS, Croghan T, Zhang L, Small PA Jr (1992) Transgenic mice lacking class I major histocompatibility complex-restricted T cells have delayed viral clearance and increased mortality after influenza virus challenge. J Exp Med 175:1143–1145PubMedCrossRefGoogle Scholar
  7. Bender BS, Bell WE, Taylor S, Small PA Jr (1994) Class I major histocompatibility complex-restricted cytotoxic T lymphocytes are not necessary for heterotypic immunity to influenza. J Infect Dis 170:1195–1200PubMedCrossRefGoogle Scholar
  8. Bix M, Raulet D (1992) Functionally conformed free class I heavy chains exist on the surface of beta 2 microglobulin negative cells. J Exp Med 176:829–834PubMedCrossRefGoogle Scholar
  9. \Christensen JP, Marker O, Thomsen AR (1994) The role of CD4+ T cells in cell-mediated immunity to LCMV: studies in MHC class I and class II deficient mice. Scand J Immunol 40:373–382PubMedCrossRefGoogle Scholar
  10. Cook, JR, Solheim JC, Connolly JM, Hansen TH (1995) Induction of peptide-specific CD8+ CTL clones in beta 2-microglobulin-deficient mice. J Immunol 154:47–57PubMedGoogle Scholar
  11. Deepe GS Jr (1994) Role of CD8+ T cells in host resistance to systemic infection with histoplasma capsulatum in mice. J Immunol 152:3491–3500PubMedGoogle Scholar
  12. DeLibero G, Flesch I, Kaufmann SHE (1988) Mycobacteria-reactive Lyt-2+ T cell lines. Eur J Immunol 18:59CrossRefGoogle Scholar
  13. Denkers EY, Gazzinelli RT, Martin D, Sher A (1993) Emergence of NK1.1+ cells as effectors of IFN-gamma dependent immunity to toxoplasma gondii in MHC class I-deficient mice. J Exp Med 178:1465–1472PubMedCrossRefGoogle Scholar
  14. Doherty PC, Hou S, Southern PJ (1993) Lymphocytic choriomeningitis virus induces a chronic wasting disease in mice lacking class I major histocompatibility complex glycoproteins. J Neuroimmunol 46:11–17PubMedCrossRefGoogle Scholar
  15. Eichelberger M, Allan W, Zijlstra M, Jaenisch R, Doherty PC (1991) Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J Exp Med 174:875–880PubMedCrossRefGoogle Scholar
  16. Emmerling P, Finger H, Bockemuhl J (1975) Listeria monocytogenes infection in nude mice. Infect Immun 12:437–439PubMedGoogle Scholar
  17. Emoto M, Neuhaus O, Emoto Y, Kaufmann SH (1996) Influence of β2-microglobulin expression on γ-interferon secretion and target cell lysis by intraepithelial lymphocytes during intestinal Listeria monocytogenes infection. Infect Immun 64:569–575PubMedGoogle Scholar
  18. Epstein SL, Misplon JA, Lawson CM, Subbarao EK, Connors M, Murphy BR (1993) Beta 2-microglobulin-deficient mice can be protected against influenza A infection by vaccination with vaccinia-influenza recombinants expressing hemagglutinin and neuraminidase. J Immunol 150:5484–5493PubMedGoogle Scholar
  19. Fiette L, Aubert C, Brahic M, Rossi CP (1993) Theiler’s virus infection of beta 2-microglobulin-deficient mice. J Virol 67:589–592PubMedGoogle Scholar
  20. Flynn JL, Goldstein MM, Triebold KJ, Koller B, Bloom BR (1992) Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection. Proc Natl Acad Sci USA 89:12013–12017PubMedCrossRefGoogle Scholar
  21. Franco MA, Greenberg HB (1995) Role of B cells and cytotoxic T lymphocytes in clearance of and immunity to rotavirus infection in mice. J Virol 69:7800–7806PubMedGoogle Scholar
  22. Gazzinelli RT, Hakim FT, Hieny S, Shearer GM, Sher A (1991) Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-γ production and protective immunity induced by an attenuated Toxoplasma gondii vaccine. J Immunol 146:286PubMedGoogle Scholar
  23. Glas R, Franksson L, Ohlen C, Hoglund P, Koller B, Ljunggren HG, Karre K (1992) Major histocompatibility complex class 1-specific and -restricted killing of beta 2-microglobulin-deficient cells by CD8+ cytotoxic T lymphocytes. Proc Natl Acad Sci USA 89:11381–11385PubMedCrossRefGoogle Scholar
  24. Gombold JL, Sutherland RM, Lavi E, Paterson Y, Weiss SR (1995) Mouse hepatitis virus A59-induced demyelination can occur in the absence of CD8+ T cells. Microbial Pathogen 18:211–221CrossRefGoogle Scholar
  25. Graham MB, Braciale VL, Braciale TJ (1994) Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection. J Exp Med 180:1273–1282PubMedCrossRefGoogle Scholar
  26. Heinzei FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM (1989) Reciprocal expression of interferon-γ or interleukin-4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med 169:59–72CrossRefGoogle Scholar
  27. Hoglund P, Sundback J, Olsson-Alheim M, Johansson M, Salcedo M, Ohlen C, Ljunggren H, Sentman C, Karre K (1997) Host MHC class I gene control of NK-cell specificity in the mouse. Immunol Rev 155:11–28PubMedCrossRefGoogle Scholar
  28. Hou S, Doherty PC, Zijlstra M, Jaenisc R, Katz JM (1992) Delayed clearance of Sendai virus in mice lacking class I MHC-restricted CD8+ T cells. J Immunol 149:1319–1325PubMedGoogle Scholar
  29. Hyland L, Hou S, Coleclough C, Takimoto T, Doherty PC (1994) Mice lacking CD8+ T cells develop greater numbers of IgA-producing cells in response to a respiratory virus infection. Virology 204:234–241PubMedCrossRefGoogle Scholar
  30. Kocks C, Gouin E, Tabouret M, Berche P, Ohayon H, Cossart P (1992) L. monocytogenes-induced actin assembly requires the actA gene product, a surface protein. Cell 68:521–531PubMedCrossRefGoogle Scholar
  31. Koller B, Marrack P, Kappler J, Smithies O (1990) Normal development of mice deficient in ß2-microglobulin, MHC class I proteins and CD8+ T cells. Science 248:1227–1230PubMedCrossRefGoogle Scholar
  32. Ladel CH, Flesch IEA, Arnoldi J, Kaufmann SHE (1994) Studies with MHC-deficient knock-out mice reveal impact of both MHC I- and MHC II-dependent T cell responses on Listeria monocytogenes infection. J Immunol 153:3116–3122PubMedGoogle Scholar
  33. Lamouse-Smith E, Clements VK, Ostrand-Rosenberg S (1993) Beta 2M-/- knockout mice contain low levels of CD8+ cytotoxic T lymphocyte that mediate specific tumor rejection. J Immunol 151:6283–6290PubMedGoogle Scholar
  34. Lavi E, Wang Q (1995) The protective role of cytotoxic T cells and interferon against coronavirus invasion of the brain. Adv Exp Med Biol 380:145–149PubMedCrossRefGoogle Scholar
  35. Lehmann-Grube F, Lohler J, Utermohlen O, Gegin C (1993) Antiviral immune responses of lymphocytic choriomeningitis virus-infected mice lacking CD8+ T lymphocytes because of disruption of the beta 2-microglobulin gene. J Virol 67:332–339PubMedGoogle Scholar
  36. Lehmann-Grube F, Dralle H, Utermohlen O, Lohler J (1994) MHC class I molecule-restricted presentation of viral antigen in beta 2-microglobulin-deficient mice. J Immunol 153:595–603PubMedGoogle Scholar
  37. Liao NS, Bix M, Zijlstra M, Jaenisch R, Raulet D (1991) MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK activity. Science 253:199–202PubMedCrossRefGoogle Scholar
  38. Mackaness GB (1962) Cellular resistance to infection. J Exp Med 118:381–406CrossRefGoogle Scholar
  39. Magee DM, Williams DM, Smith JG, Bleicker CA, Grubbs BG, Schachter J, Rank RG (1995) Role of CD8 T cells in primary chlamydia infection. Infect Immun 63:516–521PubMedGoogle Scholar
  40. Malik A, Egan JE, Houghten RA, Sadoff JC, Hoffman SL (1991) Human cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein. Proc Natl Acad Sci USA 88:3300–3305PubMedCrossRefGoogle Scholar
  41. Manickan E, Rouse BT (1995) Roles of different T-cell subsets in control of herpes simplex virus infection determined by using T-cell-deficient mouse-models. J Virol 69:8178–8179PubMedGoogle Scholar
  42. Marusic-Galesic S, Udaka K, Walden P (1993) Increased number of cytotoxic T cells within CD4+8- T cells in beta 2-microglobulin, major histocompatibility complex class I-deficient mice. Eur J Immunol 23:3115–3119PubMedCrossRefGoogle Scholar
  43. McDermott MR, Lukacher AE, Braciale VL, Braciale TJ, Bienenstock J (1987) Characterization and in vivo distribution of influenza-virus-specific T-lymphocytes in the murine respiratory tract. Am Rev Respir Dis 135:245–249PubMedGoogle Scholar
  44. Mielke MEA, Ehlers S, Hahn H (1993) The role of cytokines in experimental listeriosis. Immunobiol 189:285–315CrossRefGoogle Scholar
  45. Miller DJ, Rivera-Quinones C, Njenga MK, Leibowitz J, Rodriguez M (1995) Spontaneous CNS remyelination in beta 2 microglobulin-deficient mice following virus-induced demyelination. J Neurosci 15:8345–8352PubMedGoogle Scholar
  46. Morrison RP, Feilzer K, Tumas DB (1995) Gene knockout mice establish a primary protective role for major histocompatibility complex class II-restricted responses in Chlamydia trachomatis genital infection. Infect Immun 63:4661–4668PubMedGoogle Scholar
  47. Muller D, Koller BH, Whitton JL, LaPan KE, Brigman KK, Frelinger JA (1992) LCMV-specific, class II-restricted cytotoxic T cells in beta 2-microglobulin-deficient mice. Science 255:1576–1578PubMedCrossRefGoogle Scholar
  48. Muller D, Chen M, Vikingsson A, Hildeman D, Pederson K (1995) Oestrogen influences CD4+ T-lymphocyte activity in vivo and in vitro in beta 2-microglobulin-deficient mice. Immunology 86:162–167PubMedGoogle Scholar
  49. Niemialtowski MG, Godfrey VL, Rouse BT (1994) Quantitative studies on CD4+ and CD8+ cytotoxic T lymphocyte responses against herpes simplex virus type 1 in normal and beta 2-m deficient mice. Immunobiol 190:183–194CrossRefGoogle Scholar
  50. Ohlen C, Hoglund P, Sentman CL, Carbone E, Ljunggren HG, Koller B, Karre K (1995) Inhibition of natural killer cell-mediated bone marrow graft rejection by allogeneic major histocompatibility complex class I, but not class II molecules. Eur J Immunol 25:1286–1291PubMedCrossRefGoogle Scholar
  51. Orme I (1994) Protective and memory immunity in mice infected with Mycobacterium tuberculosis. Immunobiol 191:503–508CrossRefGoogle Scholar
  52. Parnes JR, Sizer KC, Seidman JG, Stallings V, Hyman R (1986) A mutational hot-spot within an intron of the mouse beta 2-microglobulin gene. EMBO J 5:103–111PubMedGoogle Scholar
  53. Polic B, Jonjic S, Pavic I, Cmkovic I, Zorica I, Hengel H, Lucin P, Koszinowski UH (1996) Lack of MHC class I complex expression has no effect on spread and control of cytomegalovirus infection in vivo. J Gen Virol 77:217–225PubMedCrossRefGoogle Scholar
  54. Quinn DG, Zajac AJ, Frelinger JA, Muller D (1993) Transfer of lymphocytic choriomeningitis disease in beta 2-microglobulin-deficient mice by CD4+ T cells. Int Immunol 5:1193–1198PubMedCrossRefGoogle Scholar
  55. Quinn D, Zajac A, Frelinger J (1995) Immune responses to LCMV in b2-microglobulin-deficient mice. Immunol Rev 148:151–169PubMedCrossRefGoogle Scholar
  56. Quinn DG, Zajac AJ, Hioe C, Frelinger J (1997) Virus-specific, CD8+ Majorhistocompatibility complex class I restricted cytotoxic T lymphocytes in LCMV infected ß2-microglobulin-deficient mice. J Virol 71:8329–8396Google Scholar
  57. Raulet DH, Spencer DM, Hsiang YH, Goldman JP, Bix M, Liao NS, Zijstra M, Jaenisch R, Correa I (1991) Control of gamma delta T-cell development. Immunol Rev 120:185–204PubMedCrossRefGoogle Scholar
  58. Roberts AD, Ordway DJ, Orme IM (1993) Listeria monocytogenes infection in beta 2 microglobulin-deficient mice. Infect Immun 61:1113–1116PubMedGoogle Scholar
  59. Rodriguez M, Dunkel AJ, Thiemann RL, Leibowit J, Zijlstra M, Jaenisch R (1993) Abrogation of resistance to Theiler’s virus-induced demyelination in H-2b mice deficient in beta 2-microglobulin. J Immunol 151:266–276PubMedGoogle Scholar
  60. Sadick MD, Heinzei FP, Holaday BJ, Pu RT, Dawkins RS, Locksley RM (1990) Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon-γ-independent mechanism. J Exp Med 171:115–127PubMedCrossRefGoogle Scholar
  61. Serody JS, Poston RM, Weinstock D, Kurlander RJ, Frelinger JA (1996) CD4+ cytolytic effectors are inefficient in the clearance of Listeria monocytogenes. Immunology 88:544–550PubMedCrossRefGoogle Scholar
  62. Serreze DV, Leiter EH, Christianson GJ, Greiner D, Roopenian DC (1994) Major histocompatibility complex class I-deficient NOD-B2m null mice are diabetes and insulitis resistant. Diabetes 43:505–509PubMedCrossRefGoogle Scholar
  63. Simon HB, Sheagren JN (1972) Enhancement of macrophages bactericidal capacity by antigenically stimulated immune lymphocytes. Cell Immunol 4:163–174PubMedCrossRefGoogle Scholar
  64. Slattery RM, Miller JF (1996) Influence of T lymphocytes and major histocompatibility complex class II genes on diabetes susceptibility in the NOD mouse. Curr Top Microbiol Immunol 206:51–66PubMedCrossRefGoogle Scholar
  65. Spriggs MK, Koller BH, Sato T, Morrissey PJ, Fanslow WC, Smithies O, Voice RF, Widmer MB, Maliszewski CR (1992) Beta 2-microglobulin-, CD8+ T-cell-deficient mice survive inoculation with high doses of vaccinia virus and exhibit altered IgG responses. Proc Natl Acad Sci USA 89:6070–6074PubMedCrossRefGoogle Scholar
  66. Su HC, Orange JS, Fast LD, Chan AT, Simpson SJ, Terhorst C, Biron CA (1994) IL-2-dependent NK cell responses discovered in virus-infected beta 2-microglobulin-deficient mice. J Immunol 153:5674–5681PubMedGoogle Scholar
  67. Sumida T, Furukawa M, Sakamoto A, Namekawa T, Maeda T, Zijlstra M, Iwamoto I, Koike T, Yoshida S, Tomioka H et al. (1994) Prevention of insulitis and diabetes in beta 2-microglobulin-deficient non-obese diabetic mice. Int Immunol 6:1445–1449PubMedCrossRefGoogle Scholar
  68. Suzuki Y, Orellana MA, Schrieber RD, Remington JS (1988) Interferon-γ: the major mediator of resistance against Toxoplasma gondii. Science 516:240–242Google Scholar
  69. Tay CH, Welsh RM, Brutkiewicz RR (1995) NK cell response to viral infections in beta 2-microglobulin-deficient mice. J Immunol 154:780–789PubMedGoogle Scholar
  70. Taylor SF, Bender BS (1995) Beta 2-microglobulin-deficient mice demonstrate class II MHC restricted anti-viral CD4+ but not CD8+ CTL against influenza-sensitized autologous splenocytes. Immunol Lett 46:67–73PubMedCrossRefGoogle Scholar
  71. Van der Heyde H, Manning DD, Roopenian DC, Weidanz WP (1993) Resolution of blood-stage malarial infections in CD8+ cell-deficient beta2-microglobulin deficient mice. J Immunol 151:3187–3191PubMedGoogle Scholar
  72. Wang B, Gonzalez A, Benoist C, Mathis D (1996) The role of CD8+ T cells in the initiation of insulin-dependent diabetes mellitus. Eur J Immunol 26:1762–1769PubMedCrossRefGoogle Scholar
  73. Weck KE, Barkon ML, Yoo LI, Speck SH, Virgin HI (1996) Mature B cells are required for acute splenic infection, but not for establishment of latency, by murine gammaherpesvirus 68. J Virol 70:6775–6780PubMedGoogle Scholar
  74. White KL, Snyder HL, Krzych U (1996) MHC class I-dependent presentation of exoerythrocytic antigens to CD8+ T lymphocytes is required for protective immunity against Plasmodium berghei. J Immunol 156:3374–3381PubMedGoogle Scholar
  75. Wicker LS, Leiter EH, Todd JA, Renjilian RJ, Peterson E, Fischer PA, Podolin PL, Zijlstra M, Jaenisch R, Peterson LB (1994) Beta 2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Diabetes 43:500–504PubMedCrossRefGoogle Scholar
  76. Zajac AJ, Muller D, Pederson K, Frelinger JA, Quinn DG (1995) Natural killer cell activity in lymphocytic choriomeningitis virus-infected beta 2-microglobulin-deficient mice. Int Immunol 7:1545–1556PubMedCrossRefGoogle Scholar
  77. Zajac AJ, Quinn DG, Cohen PL, Frelinger JA (1996) Fas-dependent CD4+ cytotoxic T-cell-mediated pathogenesis during virus infection Proc Natl Acad Sci USA 93:14730–14735PubMedCrossRefGoogle Scholar
  78. Zijlstra M, Bix M, Simister N, Loring J, Raulet D, Jaenisch R (1989) ß2 Microglobulin deficient mice lack CD4-CD8+ cytolytic T cells. Nature 344:742–745CrossRefGoogle Scholar
  79. Zinkemagel RM (1996) Immunology taught by viruses. Science 271:173–178CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • Jeffrey A. Frelinger
    • 1
  • Jonathan Serody
    • 2
  1. 1.Department of Microbiology and ImmunologyUniversity of North CarolinaChapel HillUSA
  2. 2.Department of MedicineUniversity of North CarolinaChapel HillUSA

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