The CD40-CD40L axis and IFN-  play critical roles in Langhans giant cell formation

Abstract

The presence of Langhans giant cells (LGCs) is one of the signatures of systemic granulomatous disorders such as tuberculosis and sarcoidosis. However, the pathophysiological mechanism leading to LGC formation, especially the contribution of the T cells abundantly found in granulomas, has not been fully elucidated. To examine the role of T cells in LGC formation, a new in vitro method for the induction of LGCs was developed by co-culturing human monocytes with autologous T cells in the presence of concanavalin A (ConA). This system required close contact between monocytes and T cells, and CD4+ T cells were more potent than CD8+ T cells in inducing LGC formation. Antibody inhibition revealed that a CD40-CD40 ligand (CD40L) interaction and IFN-γ were essential for LGC formation, and the combination of exogenous soluble CD40L (sCD40L) and IFN-γ efficiently replaced the role of T cells. Dendritic cell-specific transmembrane protein (DC-STAMP), a known fusion-related molecule in monocytes, was up-regulated during LGC formation. Moreover, knock-down of DC-STAMP by siRNA inhibited LGC formation, revealing that DC-STAMP was directly involved in LGC formation. Taken together, these results demonstrate that T cells played a pivotal role in a new in vitro LGC formation system, in which DC-STAMP was involved, and occurred via a molecular mechanism that involved CD40-CD40L interaction and IFN-γ secretion.

The Tuberculous Granuloma: An Unsuccessful Host Defence Mechanism Providing a Safety Shelter for the Bacteria?

“…Our team recently reported that the fusion process could be triggered in a TLR2-dependent cell activation by mycobacterial lipomannan (but not lipoarabinomannan), and that this process was dependent on a ß1 integrin/ADAM9 pathway [47]. Another very recent study showed that the coculture of macrophages with activated T cells can lead to MGC formation through CD40/CD40L interaction and IFN- γ secretion [48]. MGCs are found only in the granulomas induced by Mtb.…”

Immunological cell type characterization and Th1–Th17 cytokine production in a mouse model of Gaucher disease

“…This observation strongly supports the predominant role of IL-23 in mediating Th17 cell response. Notably, the GC-mediated DC-T cell interaction in promoting the Th1 and Th17 responses in 9V/null mice may also relate to its efficiency in inducing the CD40L expression, as CD40-CD40L crosstalk is important to the Th1 and Th17 responses [30, 47–50]. These results support GC as promoting the engagement of CD40 through T cell CD40L; This is a critical step for T cells activation and up-regulation of Th1 and Th17 immune responses [30, 43, 51, 52].…”

Macrophage and Multinucleated Giant Cell Classification

“…The macrophage maturation factors alone do not induce fusion [85,86]. Stimulation with IL-4 or IL-13 in vitro results predominantly in foreign-body giant cell formation, while stimulation with IFNγ results predominantly in Langhans giant cell formation [87]. Other factors suggested to stimulate MGC formation include α-tocopherol (a form of vitamin E) [88], calcitriol (1,25-dihydroxyvitamin D3) [89], phorbol 12-myristate 13-acetate [90], and T-cell mitogenic plant lectins concanavalin A and phytohemagglutinin [91].…”