T-cell lung granulomas induced by sepharose-coupled Mycobacterium tuberculosis protein antigens: immunosuppressive phenomena reversed with cyclophosphamide and indomethacin

Abstract

We induced lung granulomas in BALB/c mice by intratracheal instillation of Sepharose beads coated with a Mycobacterium tuberculosis protein extract. Granulomas composed of macrophages and lymphocytes were induced. The granulomatous reaction reached its peak 3-7 days after challenge and lasted for approximately 1 month. Immunolabelling of tissue sections and bronchial washings revealed that granulomas were predominantly composed of T lymphocytes with the cytotoxic-suppressor phenotype (CD8+). Granulomas were associated with a significant decrease in anti-mycobacterial immunity manifested by a drop in delayed-type hypersensitivity reactions and antibody titres. The immunosuppressive phenomena were abolished with cyclophosphamide or indomethacin. Control granulomas induced with methylated bovine serum albumin (BSA) were smaller and composed by similar numbers of CD4+ and CD8+ cells. BSA granulomas did not alter antibody titres but they decreased delayed-type hypersensitivity to BSA which was restored to normal with indomethacin but not with cyclophosphamide. Our findings show that mycobacterial proteins anchored to Sepharose beads are granulomatogenic and that they preferentially recruit CD8+ cells which, together with locally produced prostaglandins, down-modulate cell-mediated and humoral immunity to mycobacterial antigens.