STUDIES ON THE MECHANISMS FOR EXPRESSION OF THE SUPPRESSOR ACTIVITY BY MYCOBACTERIUM AVIUM COMPLEX-INDUCED IMMUNOSUPPRESSIVE MACROPHAGES

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We studied profiles of cell-to-cell interaction of immunosuppressive macrophages (MΦs) induced by Mycobacterium avium complex infection (MAC-MΦs) with target T cells. First, experiments using a dual chamber system indicated that cell contact is required for full expression of the MΦ suppressor activity against concanavalin A (Con A)-induced T cell mitogenesis. MAC-MΦs displayed suppressor activity in an H-2 allele-independent manner, indicating that MHC molecules are not required for such cell contact. The suppressor activity of MAC-MΦs was markedly reduced by treatment with either paraformaldehyde, cytochalasin B, or colchicine, indicating that vital membrane functions of MAC-MΦs are required for the expression of suppressor activity. Second, blocking experiments using antibodies (Abs) against adhesion molecules indicated that B7-1 but none of B7-2, ICAM-1, or VCAM-1 molecules were required for expression of the MΦ suppressor activity. Indeed, MAC-MΦs displayed markedly increased B7-1 … More expression in parallel with the acquisition of the suppressor activity. Third, Ab-blocking of CD28 and CTLA-4 on target T cells did not reduce the suppressor activity of MAC-MΦs. Thus, there may exist another type of surface molecules on target T cells, that serves as a receptor for B7-1-mediated suppressive signals from MAC-MΦs. Fourth, precultivation of splenocytes (SPCs) with MAC-MΦs reduced Con A-induced mitogenesis but not phorbol myristate acetate (PMA)/Ca^<2+> ionophore A23187-elicited proliferation of the SPCs. Thus, when resting T cells receive suppressive signals from MAC-MΦs via cell contact and are subsequently subjected to a Con A stimulatory signal, MΦ-derived suppressor signals may interfere with the upstream events of protein kinase C(PKC) activation or intracellular Ca^<2+> mobilization. Indeed, Co-cultivation of splenic T cells with MAC-MΦs reduced Con A-induced PKC activation and its translocation to the cell membrane in the T cells. Fifth, when MAC-MΦs came in contact with T cells which had been subjected to PMA/A23187 signals, T cell proliferative response was strongly suppressed. Thus, when PMA/A23187-induced signal transduction events have already been mobilized in target T cells, MAC-MΦ suppressor signals can also cross-talk with the downstream pathways of PKC activation or Ca^<2+> mobilization. Less