Down-regulation of mannosyl receptor-mediated endocytosis and antigen F4/80 in bacillus calmette-guerin-activated mouse macrophages. Role of T lymphocytes and lymphokines

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Abstract
BCG infection alters the surface and endocytic properties of mouse peritoneal macrophages (PM) compared with thioglycollate-elicited (TPM) or resident PM (RPM). Expression of Ia antigen (Ag) is enhanced up to 4-fold, but plasma membrane receptors that mediate binding and uptake of mannosyl/fucosyl-terminated glycoconjugates (MFR), Fc receptors and the macrophage (m.vphi.)-specific Ag F4/80 are reduced by 50-80%. Levels of Mac-1 remain relatively stable. These changes are accompanied by enhanced secretion of O2-, after further stimulation with phorbyl myristate acetate, and of plasminogen activator. Both these products are released by TPM but not RPM. The characteristic surface phenotype of BCG-PM can also be induced by injection of Corynebacterium parvum [Propionibacterium acnes], another m.vphi.-activating agent, but not by thioglycollate broth, lipopolysaccharide or proteose peptone. Purified protein derivative (PPD) and N-acetylmuramyl-L-alanyl-D-isoglutamine .cntdot. 2H2O are soluble agents with partial activity. Alteration of m.vphi. markers by BCG infection depends on T lymphocyte function, although studies with nude mice indicate that other pathways may also serve to modify the surface of the m.vphi.. M.vphi. from uninfected animals displayed all markers of activation after adoptive transfer of specifically-sensitized lymphocytes with PPD, i.p., or after co-cultivation. Treatment of primed lymphocytes with anti-Thy-1 antibody and complement ablated this effect. Lymphokines obtained by Ag or mitogen stimulation induced similar changes in TPM and RPM. Mannose-specific endocytosis decayed rapidly(half-time .simeq. 16 h) and stabilized at .apprx. 25% of control values. Single-cell analysis showed that residual MFR activity was uniform in the target population. Loss of Ag F4/80 after activation by lymphocyte and PPD was less marked than after infection (35% vs. 80%), unlike MFR activity, which declined to a similar extent. Induction of m.vphi. Ia by lymphokine reached a peak after 2-3 days and was lost within 2 days of its removal. Recovery of MFR and F4/80 was incomplete under these conditions. These studies establish that activated m.vphi. known to display enhanced antimicrobial/anticellular activity express markedly different surface properties distinct from elicited or resident cells. The role of antigen-stimulated T cell products in regulating m.vphi. function is confirmed, and down-regulation of mannosyl-receptor-mediated endocytosis provides a sensitive, quantitative and cell-specific new marker to study their properties and mechanism of action. Extensive, but selective remodeling of m.vphi. plasma membrane structure could play an important role in controlling recognition and effector mechanisms of the activated m.vphi.