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Cutting Edge: High Molecular Weight Hyaluronan Promotes the Suppressive Effects of CD4⁺CD25⁺ Regulatory T Cells¹

Benaroya Research Institute, Seattle, WA 98101

Hyaluronan is a glycosaminoglycan present in the extracellular matrix. When hyaluronan is degraded during infection and injury, low m.w. forms are generated whose interactions influence inflammation and angiogenesis. Intact high m.w. hyaluronan, conversely, conveys anti-inflammatory signals. We demonstrate that high m.w. hyaluronan enhances human CD4⁺CD25⁺ regulatory T cell functional suppression of responder cell proliferation, whereas low m.w. hyaluronan does not. High m.w. hyaluronan also up-regulates the transcription factor FOXP3 on CD4⁺CD25⁺ regulatory T cells. These effects are only seen with activated CD4⁺CD25⁺ regulatory T cells and are associated with the expression of CD44 isomers that more highly bind high m.w. hyaluronan. At higher concentrations, high m.w. hyaluronan also has direct suppressive effects on T cells. We propose that the state of HA in the matrix environment provides contextual cues to CD4⁺CD25⁺ regulatory T cells and T cells, thereby providing a link between the innate inflammatory network and the regulation of adaptive immune responses.

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 National Institutes of Health Grants DK46635 (to J.H.B.), HL18645, and DK53004 and funds from the Juvenile Diabetes Research Foundation (The Center for Translational Research at Benaroya Research Institute, Seattle, WA).

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: HA; hyaluronan; HMW-HA, high m.w. HA; LMW-HA; low m.w. HA; T_R, CD4⁺CD25⁺ regulatory T cell.