Humoral and cellular immunity in secondary infection due to murine Chlamydia trachomatis.
A murine model of pneumonia due to the mouse pneumonitis agent (MoPn [murine Chlamydia trachomatis]) in mice deficient in CD4+ T-cell function (major histocompatibility complex [MHC] class II function [class II-/-], CD8+ T-cell function (beta2-microglobulin deficient, MHC class I deficient [Beta2m-/-]), B-cell function (C57BL/10J-Igh(tm1Cgn) [Igh-/-]), and gamma interferon (IFN-gamma) (C57BL/6-Ifg(tm1) [Ifg-/-]) or interleukin-4 (C57BL/6J(tm1Cgn29) [IL4-/-]) production was employed to determine if each of these mechanisms was critical to resistance against reinfection by C. trachomatis or if alternate compensatory mechanisms existed in their absence which could potentially be exploited in vaccine development. Resistance to reinfection with MoPn was heavily dependent on CD4+ T cells. CD4 T-cell-deficient MHC class II-/- mice were very susceptible to reinfection with MoPn, showing the critical importance of this cell to resistance. These mice lacked antibody production but did produce IFN-gamma, apparently by mechanisms involving NK and CD8+ T cells. Neutralization of IFN-gamma in these mice led to a borderline increase in susceptibility, showing a possible role (albeit small) of this cytokine in this setting. Tumor necrosis factor alpha (TNF-alpha) was also present at increased levels in these mice. Igh-/- B-cell-deficient mice which produce no antibody to MoPn were only modestly more susceptible to reinfection than immunized B-cell-intact controls, showing that antibody, including lung immunoglobulin A, is not an absolute requirement for relatively successful host defense in this setting. Levels of lung IFN-gamma and TNF-alpha were elevated in Igh-/- mice compared to those in controls. IL-4-/- mice (deficient in Th2 function) could develop normal resistance to reinfection with MoPn. Conversely, normal mice rendered partially IFN-gamma deficient by antibody depletion were somewhat impaired in their ability to develop acquired immunity to MoPn, again indicating a role for this cytokine in host defense against rechallenge. Of most importance, however, congenitally IFN-gamma-deficient Ifg-/- mice (which have elevated levels of other cytokines, including TNF-alpha and granulocyte-macrophage colony-stimulating factor) are paradoxically more resistant to MoPn rechallenge than controls, showing that IFN-gamma is not an absolute requirement for acquired resistance and implying the presence of very effective compensatory host defense mechanism(s). In vivo depletion of TNF-alpha significantly increased MoPn levels in the lungs in these mice. Thus, resistance to reinfection in this model is flexible and multifactorial and is heavily dependent on CD4+ T cells, with a probable role for IFN-gamma and TNF-alpha and a possible modest role for Th1-dependent antibody. Since IFN-gamma was dispensable in host defense, the highly effective mechanism or mechanisms which can compensate for its absence (which include TNF-alpha) deserve further study.
Williams
D M
DM
Audie L. Murphy Memorial Veterans Hospital, and Department of Medicine, University of Texas Health Sciences Center at San Antonio, 78284, USA.
Grubbs
B G
BG
Pack
E
E
Kelly
K
K
Rank
R G
RG
D000818:Animals; D000907:Antibodies, Bacterial / Q000032:analysis; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002690:Chlamydia Infections / Q000276:immunology*; D002692:Chlamydia trachomatis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis; D006367:HeLa Cells; D006801:Humans; D007111:Immunity, Cellular; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000276:immunology; D012008:Recurrence; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000907:Antibodies, Bacterial; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor