TNF-α is a critical negative regulator of type 1 immune activation during intracellular bacterial infection

Abstract

TNF-α has long been regarded as a proimmune cytokine involved in antimicrobial type 1 immunity. However, the precise role of TNF-α in antimicrobial type 1 immunity remains poorly understood. We found that TNF-α-deficient (TNF -/-) mice quickly succumbed to respiratory failure following lung infection with replication-competent mycobacteria, because of apoptosis and necrosis of granuloma and lung structure. Tissue destruction was a result of an uncontrolled type 1 immune syndrome characterized by expansion of activated CD4 and CD8 T cells, increased frequency of antigen-specific T cells, and overproduction of IFN-γ and IL-12. Depletion of CD4 and CD8 T cells decreased IFN-γ levels, prevented granuloma and tissue necrosis, and prolonged the survival of TNF -/-hosts. Early reconstitution of TNF-α by gene transfer reduced the frequency of antigen-specific T cells and improved survival. TNF-α controlled type 1 immune activation at least in part by suppressing T cell proliferation, and this suppression involved both TNF receptor p55 and TNF receptor p75. Heightened type 1 immune activation also occurred in TNF -/-mice treated with dead mycobacteria, live replication-deficient mycobacteria, or mycobacterial cell wall components. Our study thus identifies TNF-α as a type 1 immunoregulatory cytokine whose primary role, different from those of other type 1 cytokines, is to keep an otherwise detrimental type 1 immune response in check.

Illuminating the Black Box of TNF Action in Tuberculous Granulomas

“…Large numbers of apoptotic macrophages and/or lymphocytes were observed in murine studies in which TNF blockade resulted in major histopathologic deterioration of lung tissue (Mohan et al, 2001;Zganiacz et al, 2004). This is in contrast to the findings that TNF induces apoptosis of human alveolar macrophages infected with M. tuberculosis in vitro (Keane et al, 2002).…”

“…Because granulomas are defective in mice that lack TNF activity, it is commonly believed that TNF orchestrates the initial formation of granulomas in mycobacterial (BCG or virulent M. tuberculosis) infections. In the absence of TNF signaling, granulomas in various tissues are present in markedly decreased numbers (Kindler et al, 1989), are smaller (Zganiacz et al, 2004), and lack cellular organization and characteristic architecture (Flynn et al, 1995). However, these studies were limited by their having to sample tissues at discrete time points after infection, making it difficult to distinguish effects of TNF on initial formation of granulomas from effects on granuloma maintenance.…”

“…In the murine model, neutralization of TNF in vitro and in vivo leads to decreased secretion of chemokines by infected macrophages and other CD11b + cells, and such a decrease may result in disruption of cell migration into and out of granulomas (Algood et al, 2004). Moreover, other work has revealed a regulatory role of TNF on IFN-g-producing CD4 + and CD8 + T cells in BCG-infected mice, in which TNF prevents T cell-dependent granuloma disintegration and inflammatory destruction of the lung tissue (Zganiacz et al, 2004).…”

“…Murine studies reveal variable increases in bacillary load when TNF is neutralized, ranging from small changes to multiple orders of magnitude (Flynn et al, 1995;Kindler et al, 1989;Zganiacz et al, 2004). In the current study, the absence of TNF signaling exerted an early effect on growth of M. marinum in macrophages in vivo and resulted in 10-fold enhancement of intracellular replication.…”

Granulomatous Inflammation in the Lungs of Mice with Systemic Candidiasis Receiving a Composition of Amphotericin B and Dialdehyde Dextran

“…Candidal inflammation of the lungs is manifested in granulomatous inflammation (GI) and occupies the first place in candidal damage to internal organs [4]. GI during candidiasis is related to persistence of yeast-like C. albicans in the vacuolar apparatus of macrophages [8,12], which makes then poorly accessible for drugs, including amphotericin B (AmB), which has several advantages over other preparations of similar action [3]. Therapy with antimycotic drugs that exhibit tropism for the vacuolar-lysosomal apparatus of phagocytes (site for persistence of C. albicans fungi) is pathogenetically substantiated [6].…”