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lüll Intact extracellular matrix and the maintenance of immune tolerance: high molecular weight hyaluronan promotes persistence of induced CD4+CD25+ regulatory T cells Bollyky PL; Falk BA; Wu RP; Buckner JH; Wight TN; Nepom GTJ Leukoc Biol 2009[Sep]; 86 (3): 567-72The 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+ T(Reg) function, and LMW-HA does not. Using a human iT(Reg) 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 T(Reg). This effect, in part, may be mediated by a role for intact HMW-HA in IL-2 production, as T(Reg) 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 T(Reg) after tissue matrix integrity has been restored.|Animals[MESH]|CD4 Antigens/*immunology[MESH]|Extracellular Matrix/*immunology[MESH]|Humans[MESH]|Hyaluronic Acid/chemistry/*pharmacology[MESH]|Immune Tolerance/*drug effects[MESH]|Interleukin-2 Receptor alpha Subunit/*immunology[MESH]|Molecular Weight[MESH]|T-Lymphocytes, Regulatory/*immunology[MESH] |