CD137 differentially regulates innate and adaptive immunity against Mycobacterium tuberculosis

Abstract

Protective immunity against Mycobacterium tuberculosis is primarily mediated by the interaction of antigen-specific T cells and antigen presenting cells, which often depends on the interplay of cytokines produced by these cells. Costimulatory signals represent a complex network of receptor–ligand interactions that qualitatively and quantitatively influence immune responses. Thus, here we investigated the function of CD137 and CD137L, molecules known to have a central role in immune regulation, during human tuberculosis (TB). We demonstrated that M. tuberculosis antigen stimulation increased both CD137 and CD137L expression on monocytes and NK cells from TB patients and healthy donors, but only up-regulated CD137 on T lymphocytes. Blockage of the CD137 pathway enhanced the levels of interferon (IFN)-γ and tumor necrosis factor (TNF)-α produced by monocytes and NK against M. tuberculosis. In contrast, CD137 blockage significantly decreased the specific degranulation of CD8+ T cells and the percentage of specific IFN-γ and TNF-α producing lymphocytes against the pathogen. Furthermore, inhibition of the CD137 pathway markedly increased T-cell apoptosis. Taken together, our results demonstrate that CD137:CD137L interactions regulate the innate and adaptive immune response of the host against M. tuberculosis.

Role of the CD137 ligand (CD137L) signaling pathway during Mycobacterium tuberculosis infection

“…Recent literature has suggested the engagement of the CD137 signaling pathway during M. tuberculosis infection in humans and mice (Fernández Do Porto et al 2011;Palma et al 2010). Our data support these earlier findings and provide insights into the mechanisms by which the CD137-CD137L system contributes to the immune resistance against M. tuberculosis.…”

“…In addition, the strikingly low levels of TNF-␣ measured in the BALF from M. tuberculosis-infected CD137L −/− mice may contribute to the greater bacterial burden and granuloma-like lesions. It has been shown that CD137L is required for sustained TNF production in macrophages (Kang et al 2007), and that blockade of CD137 leads to reduced TNF production by T cells from TB patients (Fernández Do Porto et al 2011). Interestingly, CD137L has recently been shown to associate with TNF receptor 1, and to utilize TNF receptor 1 for its signal transduction .…”

“…Among them, expression of the co-stimulatory molecule CD137 was detected in a sub-population of T lymphocytes infiltrating lung tuberculous granulomas in TB patients (Boussaud et al 1998). In addition, the CD137 signaling pathway was recently shown to be involved in the regulation of both the innate and adaptive immune responses against M. tuberculosis in human (Fernández Do Porto et al 2011). CD137, also called 4-1BB or TNFRSF9, is a member of the TNFR superfamily and is mainly expressed by activated T cells but can also be expressed by DCs, natural killer cells, neutrophils and endothelial cells.…”

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

“…A function for 4-1BB at earlier thymic differentiation stages has not been reported; however, some studies have shown that 4-1BB can regulate TNF-a expression (46,47) and vice versa (48), suggesting a possible link between the two. Overexpression of TNF-a under control of its natural promoter has been reported to block early thymocyte development at the DN1 to DN2 stage, promoting accelerated thymic atrophy (49) and mirroring our own observations in the NOD thymus.…”

Involvement of the 4-1BB/4-1BBL Pathway in Control of Monocyte Numbers by Invariant NKT Cells

“…A total of 2 3 10 5 monocytes were plated in round-bottom 96-well plates at differing ratios to iNKT cells as described in Results. 4-1BB blocking Ab (4B4-1; BD, Bergen County, NJ) and 4-1BB ligand blocking Ab (C65-485; BD) (30) were added at the beginning of the coculture at 5 mg/ml each. When indicated in text, CD1d blocking Ab (CD1d42; BD Pharmingen, Oxford, U.K.) was added at 10 or 25 mg/ml.…”