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 func tion (major histocompatibility complex [MHC] class II function [class II-/-], CD8(+) T-cell function (beta(2)-microglobulin deficient, MHC c lass I deficient [Beta(2)m(-/-)]), B-cell function (C57BL/10J-Igh(tm1C gn) [Igh(-/-)]), and gamma Interferon (IFN-gamma) (C57BL/6-Ifg(tm1) [I fg(-/-)]) or interleukin-4 (C57/BLtm1Cgn129 [IL4(-/-)]) production was employed to determine if each of these mechanisms was critical to res istance against reinfection by C. trachomatis or if alternate compensa tory mechanisms existed in their absence which could potentially be ex ploited in vaccine development. Resistance to reinfection with MoPn wa s heavily dependent on CD4(+) T cells. CD4 T-cell-deficient MHC class II-/- mice sere very susceptible to reinfection with MoPn, showing the critical importance of this cell to resistance. These mice lacked ant ibody production hut did produce IFN-gamma, apparently hy mechanisms i nvolving NK and CD8(+) T cells. Neutralization of IFN-gamma in these m ice led to a borderline increase in susceptibility showing a possible role (albeit small) of this cytokine in this setting, Tumor necrosis f actor 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-c ell-intact controls, shelving that antibody, including lung immunoglob ulin A, if not an absolute requirement for relatively successful host defense in this setting. Levels of lung IFN-gamma and TNF-alpha were e levated in Igh(-/-) miff compared to those in controls. IL-4(-/-) mice (deficient in Th2 function) could develop normal resistance to reinfe ction with MoPn. Conversely, normal mice rendered partially IFN-gamma deficient by antibody depletion were somewhat impair ed in their abili ty to develop acquired immunity to MoPn, again indicating a role for t his cytokine in host defense against rechallenge. Of most importance, however, congenitally IFN-gamma-deficient Ifg(-/-) mice (which have el evated levels of other cytokines, including TNF-alpha and granulocyte- macrophage colony-stimulating fatter) are paradoxically more resistant to MoPn rechallenge than controls, showing that IFN-gamma if not an a bsolute requirement for acquired resistance and implying the presence of very effective compensatory host defense mechanism(s). In vivo depl etion 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 def ense, the highly effective mechanism or mechanisms which can compensat e for its absence (which include TNF-alpha) deserve further study.