T-Cell Hyporesponsiveness Induced by Activated Macrophages through Nitric Oxide Production in Mice Infected withMycobacterium tuberculosis

ABSTRACTIn active tuberculosis, T-cell response to Mycobacterium tuberculosisis known to be reduced. In the course ofMycobacterium tuberculosisinfection in mice, we observed that T-cell proliferation in response to M. tuberculosispurified protein derivative (PPD) reached the maximum level on day 7, then declined to the minimal level on day 14, and persisted at a low level through day 28 postinfection. The frequency of PPD-specific CD4 T cells in the spleen on day 28 decreased to one-sixth on day 7. To further investigate the mechanism of this T-cell hyporesponsiveness, we next analyzed the suppressive activity of spleen macrophages on T-cell function. The nonspecific proliferative response of naive T cells and the PPD-specific proliferative response of T cells were suppressed by day 28 macrophages, but not by day 7 macrophages or naive macrophages. This reduction of proliferative response was restored by addition of nitric oxide synthesis inhibitor, NG-monoethyl-l-arginine monoacetate, but not by monoclonal antibody against interleukin 10 or transforming growth factor β. These data indicate that the macrophages from mice chronically infected with M. tuberculosissuppress T-cell response through production of nitric oxide, suggesting that nitric oxide-induced elimination mediated by activated macrophages may reduce the T-cell response and the number of mycobacterium-specific CD4 T cells in vivo.