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ARS Home » Northeast Area » Beltsville, Maryland (BARC) » Beltsville Agricultural Research Center » Animal Parasitic Diseases Laboratory » Research » Publications at this Location » Publication #341724

Title: STAT6 and Furin are successive triggers for the production of TGFß by T cells

item LI, YUE - University Of Iowa
item LIU, WEIREN - University Of Iowa
item GUAN, XIAOQUN - University Of Iowa
item TRUSCOTT, JAMIE - University Of Iowa
item CREEMERS, JOHN - Laboratory For Biochemical Neuroendocrinology, Department Of Human Genetics
item CHEN, HUNG-LIN - University Of Iowa
item PESU, MARKO - University Of Tampere
item EL ABIAD, RAMI - University Of Iowa
item KARAKAY, BAHRI - University Of Iowa
item Urban, Joseph
item ELLIOTT, DAVID - University Of Iowa
item KAPLAN, MARK - Indiana University School Of Medicine
item BLAZER, BRUCE - University Of Minnesota
item INCE, M NEDIM - University Of Iowa

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/15/2017
Publication Date: 11/1/2018
Citation: Li, Y., Liu, W., Guan, X., Truscott, J., Creemers, J.W., Chen, H., Pesu, M., El Abiad, R., Karakay, B., Urban Jr, J.F., Elliott, D.E., Kaplan, M.H., Blazer, B.R., Ince, M. 2018. STAT6 and Furin are successive triggers for the production of TGFß by T cells. Journal of Immunology. 201(9):2612-2623.

Interpretive Summary: Bone marrow and hematopoietic stem cell transplantation are used for the treatment of some disorders that require re-population of a subject with naive cells but the donor immune cells may react against the host resulting in severe graft-versus-host disease (GVHD). Treatment options generally employ the use of immune-suppressive steroids that can have limited benefits and cause severe toxicity. An alternative approach is to regulate lethal GVHD using regulatory T cells (Tregs) or T helper 3 cells (Th3) that suppress inflammation. Production of transforming growth factor-ß (TGF) by Th3 is a key secreted protein that can regulate inflammation. Intestinal worms naturally stimulate Th3 cells and regulate immune-mediated disorders. Scientists at the University of Iowa and USDA/ARS in Beltsville showed that a worm-induced factor called STAT6 activates the production of TGF pro-peptide (pro-TGFß) that, in turn, is cleaved by an enzyme called furin to produce the active compound involved in regulation of inflammation. Thus, the regulatory pathway necessary to generate TGF-producing Th3 cells is a two-step process of STAT6 induction and furin activation. This information is important to scientists interested in the modulating effects of worm parasites on the host, and to clinicians interested in using these pathways to regulate inflammation and reduce disease.

Technical Abstract: Production of transforming growth factor-ß (TGF) by T helper 3 (Th3) cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. However, the molecular mechanisms that lead to the commitment of Th3 cells remain unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 as well as Th3 cells and regulate immune-mediated disorders. We show that the Th2 cell-specific transcription factor STAT6 is necessary and sufficient for the expression of TGF pro-peptide (pro-TGFß) in T cells. STAT6 is also necessary for several helminth-triggered events, such as the maturation of Th3 cells and TGFß-dependent suppression of alloreactive inflammation in graft-versus-host disease (GVHD). Besides STAT6, helminth-induced secretion of active TGFß requires cleavage of pro-TGF by the endopeptidase furin. Thus - for the immune regulatory pathway necessary to generate TGF-producing Th3 cells - our results support a two-step model, consisting of STAT6 and furin.