Fibronectin is a TH1-specific molecule in human subjects.
BACKGROUND
T(H)1 cell-mediated immunity is essential for host defense against a variety of intracellular pathogens, such as mycobacteria, salmonella, and Leishmania species. A major T(H)1-mediated effector mechanism involves the IFN-gamma-induced killing of the pathogen by infected macrophages.


OBJECTIVE
The range of known T(H)1-specific effector molecules is limited, especially in human subjects. We sought to identify novel effector molecules that might be involved in T(H)1-mediated pathogen clearance.


METHODS
We performed microarray-based analysis of human T(H)1 and T(H)2 cells to identify T(H)1-specific molecules. These analyses identified the extracellular matrix molecule fibronectin as a highly expressed T(H)1-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 T(H)1 cells constitutively express and secrete fibronectin after in vitro differentiation from naive precursors. Furthermore, we demonstrate that ex vivo human T(H)1 cells selectively express fibronectin when compared with T(H)2 cells. The predominant isoform of fibronectin expressed by T(H)1 cells contains additional domains of the protein responsible for alpha4beta1 integrin binding and activation of Toll-like receptor 4. We show that treatment of monocytes with T(H)1 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 T(H)1 cells involved in pathogen eradication.
Sandig
Hilary
H
Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, United Kingdom.
McDonald
Joanne
J
Gilmour
Jane
J
Arno
Matthew
M
Lee
Tak H
TH
Cousins
David J
DJ
D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020033:Protein Isoforms / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
D005353:Fibronectins; D039041:Integrin alpha4beta1; D015850:Interleukin-6; D020033:Protein Isoforms; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D016753:Interleukin-10