CD4(-LYMPHOCYTE DEPLETION ATTENUATES LIPOPOLYSACCHARIDE-INDUCED TUMOR-NECROSIS-FACTOR SECRETION BY ALVEOLAR MACROPHAGES IN THE MOUSE() T)

Mechanisms underlying the control of cytokine secretion by alveolar ma crophages are not fully understood. We hypothesized that T lymphocytes or their products modulate the capacity of alveolar macrophages to re lease cytokines in response to an exogenous stimulus. In this study, w e investigated the role of lymphocytes expressing surface CD4 (CD4(+)) antigen in the regulation of tumor necrosis factor alpha (TNF-alpha) secretion by alveolar macrophages. Specific pathogen-free male BALB/c mice were injected intraperitoneally with 0.3 mg monoclonal anti-CD4 a ntibody or phosphate-buffered saline. Depletion of CD4(+) splenic lymp hocytes was confirmed 6 days later by now cytometry. On day 6, mice we re challenged intratracheally with E. coli lipopolysaccharide (LPS, 1- 100 mu g/100 g BW) or phosphate-buffered saline. The lungs were lavage d 3 h later and the broncholveolar lavage fluid assessed for TNF activ ity and cell recovery (total and differential). No TNF was detected in the lavage fluid of animals pretreated with antibody or phosphate-buf fered saline and given phosphate-buffered saline intratracheally. Howe ver, the saline-treated mice challenged with LPS (100 mu g/100 g BW) r eleased 3.76 +/- 0.18 ng TNF/ml bronchoalveolar lavage fluid. In contr ast, mice depleted of CD4(+) T lymphocytes released almost 50 % less T NF (1.94 +/- 0.23 ng TNF/ml lavage fluid, p < 0.001) in response to th e same dose of LPS. Administration of denatured monoclonal anti-CD4 an tibody did not significantly alter LPS-stimulated TNF release by alveo lar macrophages compared to the non-CD4-depleted (phosphate-buffered s aline-treated) LPS-challenged group. The decrease in TNF activity in l avage fluid of CD4(+)-depleted mice was not caused by a shift in peak TNF activity or nonspecific effects of the antibody. The CD4(+)-deplet ed mice challenged with LPS recruited significantly fewer polymorphonu clear leukocytes into the lungs compared with the non-CD4(+)-depleted mice challenged with the same dose of LPS. Pretreatment of the deplete d mice with recombinant murine interferon-gamma (rmIFN-gamma) before i ntratracheal LPS challenge upregulated the alveolar macrophage TNF rel ease to levels seen in normal mice treated with LPS (4.16 +/- 0.50 in rmIFN-gamma treated versus 3.76 + 0.18 ng/ml in control), as well as p olymorphonuclear leukocyte recruitment into the lungs. These data sugg est that CD4(+) T lymphocytes modulate the ability of alveolar macroph ages to secrete TNF and recruit polymorphonuclear leukocytes in respon se to an exogenous stimulus, such as LPS, perhaps through the in vivo release of T cell-derived cytokines, such as IFN-gamma. Impaired secre tion of TNF by alveolar macrophages may be one possible explanation fo r the altered host defense associated with CD4(+) T lymphocyte deficie ncy states.