Miltenyi Biotec GmbH
Originally published online as doi:10.1189/jlb.0109001 on April 28, 2009

Published online before print April 28, 2009
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(Journal of Leukocyte Biology. 2009;86:567-572.)
© 2009 Society for Leukocyte Biology

Intact extracellular matrix and the maintenance of immune tolerance: high molecular weight hyaluronan promotes persistence of induced CD4+CD25+ regulatory T cells

Paul L. Bollyky1, Ben A. Falk, Rebecca P. Wu, Jane H. Buckner, Thomas N. Wight and Gerald T. Nepom

Benaroya Research Institute, Seattle, Washington, USA

1. Correspondence: Benaroya Research Institute, 1201 Ninth Ave., Seattle, WA 98101, USA. E-mail: pbollyky{at}benaroyaresearch.org

The composition of the ECM provides contextual cues to leukocytes in inflamed and healing tissues. One example of this is HA, where LMW-HA, generated during active inflammation, is a TLR ligand and an endogenous "danger signal," and HMW-HA, predominant in healing or intact tissues, functions in an inverse manner. Our data suggest that HMW-HA actively promotes immune tolerance by augmenting CD4+CD25+ TReg function, and LMW-HA does not. Using a human iTReg model, we demonstrate that HMW-HA but not LMW-HA provides a costimulatory signal through cross-linking CD44 which promotes Foxp3 expression, a critical signaling molecule associated with TReg. This effect, in part, may be mediated by a role for intact HMW-HA in IL-2 production, as TReg are highly IL-2-dependent for their survival and function. We propose that HMW-HA contributes to the maintenance of immune homeostasis in uninjured tissue and effectively communicates an "all-clear" signal to down-regulate the adaptive immune system through TReg after tissue matrix integrity has been restored.

Key Words: autoimmunity • IL-2 • TReg