THE MOLECULAR MECHANISM OF T-CELL CONTROL OF CHLAMYDIA IN MICE - ROLEOF NITRIC-OXIDE

T-cell mediated immunity (CMI) is crucial for protection against genit al chlamydial infection in mice. To define the underlying molecular me chanism for this protection, several T-cell clones generated against t he Chlamydia trachomatis agent of mouse pneumonitis (MoPn) were analys ed in an in vitro model of the mucosal epithelium, the polarized epith elial-lymphocyte co-culture (PELC) system, for immunobiological functi ons that correlated with chlamydial inhibition. The six clones analyse d were classified as protective or non-protective on the basis of thei r ability to cure genital chlamydial infection in syngeneic mice. The results revealed a direct relationship between the ability of a clone to protect in vivo and to inhibit the multiplication of MoPn in vitro. Also, the protective ability of a clone correlated with its capacity to elaborate relatively high levels of interferon-gamma (IFN-gamma) an d to induce nitric oxide (NO) production. Moreover, neutralizing anti- IFN-gamma antibodies used alone at 50 mu g/ml or in combination with a nti-tumour necrosis-factor (TNF-alpha), and the L-arginine analogue an d NO synthase inhibitor, N-G-monomethyl-L-arginine monoacetate (MLA), could significantly suppress the ability of protective clones to inhib it MoPn in epithelial cells. The results suggested that the IFN-gamma- inducible NO synthease pathway is important for chlamydial control in mice. Furthermore, IFN-gamma could stimulate infected murine epithelia l cells (line TM3) to secrete NO, resulting in inhibition of MoPn grow th. However, the degree of MoPn inhibition obtained with IFN-gamma alo ne was less than that observed when T cells were co-cultured with infe cted epithelial cells. T-cell-derived NO could partly explain the enha nced chlamydial inhibition when T cells were co-cultured with infected epithelial cells. These results are consistent with the hypothesis th at, besides T-cell-derived IFN-gamma, other factors associated with ly mphoepithelial interactions are likely to contribute an important role in chlamydial control by T cells in mice.