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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900191v1 183/4/2232    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Bollyky, P. L. Articles by Nepom, G. T. PubMed PubMed Citation Articles by Bollyky, P. L. Articles by Nepom, G. T.

CD44 Costimulation Promotes FoxP3⁺ Regulatory T Cell Persistence and Function via Production of IL-2, IL-10, and TGF-β¹

Benaroya Research Institute, Seattle, WA 98101

Work by our group and others has demonstrated a role for the extracellular matrix receptor CD44 and its ligand hyaluronan in CD4⁺CD25⁺ regulatory T cell (Treg) function. Herein, we explore the mechanistic basis for this observation. Using mouse FoxP3/GFP⁺ Treg, we find that CD44 costimulation promotes expression of FoxP3, in part through production of IL-2. This promotion of IL-2 production was resistant to cyclosporin A treatment, suggesting that CD44 costimulation may promote IL-2 production through bypassing FoxP3-mediated suppression of NFAT. CD44 costimulation increased production of IL-10 in a partially IL-2-dependent manner and also promoted cell surface TGF-β expression. Consistent with these findings, Treg from CD44 knockout mice demonstrated impaired regulatory function ex vivo and depressed production of IL-10 and cell surface TGF-β. These data reveal a novel role for CD44 cross-linking in the production of regulatory cytokines. Similar salutary effects on FoxP3 expression were observed upon costimulation with hyaluronan, the primary natural ligand for CD44. This effect is dependent upon CD44 cross-linking; while both high-molecular-weight hyaluronan (HA) and plate-bound anti-CD44 Ab promoted FoxP3 expression, neither low-molecular weight HA nor soluble anti-CD44 Ab did so. The implication is that intact high-molecular weight HA can cross-link CD44 only in those settings where it predominates over fragmentary LMW-HA, namely, in uninflamed tissue. We propose that intact but not fragmented extracellular is capable of cross-linking CD44 and thereby maintains immunologic tolerance in uninjured or healing tissue.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (DK46635, HL18645, and DK53004) and the Juvenile Diabetes Research Institute (The Center for Translational Research at Benaroya Research Institute. P.L.B. is supported by National Institutes of Health K-08 Grant DK080178-01 and a National Institutes of Health LRP grant.

² Address correspondence and reprint requests to Dr. Paul L. Bollyky, Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101. E-mail address: pbollyky{at}benaroyaresearch.org

³ Abbreviations used in this paper: Treg, CD4⁺CD25⁺ regulatory T cell; ECM, extracellular matrix; HA, hyaluronan; HMW-HA, high-molecular-weight HA; LMW-HA, low-molecular-weight HA; WT, wild type.

⁴ The online version of this article contains supplemental material.