Fibronectin is a TH1-specific molecule in human subjects

Background: TH1 cell-mediated immunity is essential for host defense against a variety of intracellular pathogens, such as mycobacteria, salmonella, and Leishmania species. A major TH1-mediated effector mechanism involves the IFN-γ-induced killing of the pathogen by infected macrophages. Objectives: The range of known TH1-specific effector molecules is limited, especially in human subjects. We sought to identify novel effector molecules that might be involved in TH1-mediated pathogen clearance. Methods: We performed microarray-based analysis of human TH1 and TH2 cells to identify TH1-specific molecules. These analyses identified the extracellular matrix molecule fibronectin as a highly expressed TH1-specific molecule. We examined the expression of fibronectin in a variety of human cell types by using real-time RT-PCR, ELISA, and Western blotting. We also studied the role of fibronectin in modulating monocyte phenotype using in vitro culture. Results: We show that human TH1 cells constitutively express and secrete fibronectin after in vitro differentiation from naive precursors. Furthermore, we demonstrate that ex vivo human TH1 cells selectively express fibronectin when compared with TH2 cells. The predominant isoform of fibronectin expressed by TH1 cells contains additional domains of the protein responsible for α4β1 integrin binding and activation of Toll-like receptor 4. We show that treatment of monocytes with TH1 cell-derived fibronectin induces expression of the proinflammatory cytokine IL-6 while inhibiting IL-10 expression. Conclusions: Because fibronectin also plays a major role in the attachment and opsonization of numerous intracellular pathogens, we propose that it might be a critical molecule produced by TH1 cells involved in pathogen eradication. © 2009 American Academy of Allergy, Asthma & Immunology.