Critical role of heme oxygenase-1 in Foxp3-mediated immune suppression

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Abstract

Foxp3, which encodes the transcription factor scurfin, is indispensable for the development and function of CD4+CD25+ regulatory T cells (Treg). Recent data suggest conversion of peripheral CD4+CD25 naı¨ve T cells to CD4+CD25+ Treg by acquisition of Foxp3 through costimulation with TCR and TGF-β or forced expression of the gene. One critical question is how Foxp3 causes T cells to become regulatory. In the present work, we demonstrate that Foxp3 can induce heme oxygenase-1 (HO-1) expression and subsequently such regulatory phenotypes as the suppression of nontransfected cells in a cell–cell contact-dependent manner as well as impaired proliferation and production of cytokines upon stimulation in Jurkat T cells. Moreover, we confirm the expression of both Foxp3 and HO-1 in peripheral CD4+CD25+ Treg and suppressive function of the cells are relieved by the inhibition of HO-1 activity. In summary, we demonstrate that Foxp3 induces HO-1 expression and HO-1 engages in Foxp3-mediated immune suppression.

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Materials and methods

Reagents and media. RPMI 1640 supplemented with 2 mM l-glutamine, 1% nonessential amino acids, 1% pyruvate, 100 U/mL penicillin, 100 μg/mL streptomycin (Life Technologies, Grand Island, NY), and 10% heat-inactivated fetal bovine serum (FBS, HyClone Laboratories, Logan, UT) was used as complete medium in all cultures. Anit-human CD3, anti-human CD28, and zinc protoporphyrin were purchased from BD Biosciences (Mountain View, CA) and Porphyrin Products (Logan, UT), respectively. Concanavalin A (Con

Induction of HO-1 expression by Foxp3 gene transfection

Jurkat T cells were transfected with Foxp3 gene, and the gene expression was confirmed by Western blot analysis (Fig. 1A). To characterize the properties of Foxp3-transfected Jurkat T cells, we assessed the production of cytokines and proliferative responses in the cells transfected with Foxp3 gene or with control gene. Upon stimulation with PMA and ionomycin, the productions of IL-2 and IFN-γ was significantly reduced in Foxp3-transfected Jurkat T cells, as compared with the cells transfected

Discussion

Identification of signals that regulate the proliferation and function of Treg is of great importance to understand the mechanisms by which the immune tolerance breaks down and the autoimmunity develops. In the present study, we have found that Foxp3 transfer into T cells can induce HO-1 expression, which is causally associated with Foxp3-mediated development of T cells with regulatory functions.

Given that Foxp3 is a highly reliable marker for Treg cells, a key issue then in defining Treg cells

Acknowledgment

This work was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare (01-PJ3-PG6-01GN09-003).

References (19)

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