Intact extracellular matrix and the maintenance of immune tolerance: high molecular weight hyaluronan promotes persistence of induced CD4+CD25+ regulatory T cells.
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+ 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.
Bollyky
Paul L
PL
Benaroya Research Institute, Seattle, WA 98101, USA. pbollyky@benaroyaresearch.org
Falk
Ben A
BA
Wu
Rebecca P
RP
Buckner
Jane H
JH
Wight
Thomas N
TN
Nepom
Gerald T
GT
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D005109:Extracellular Matrix / Q000276:immunology*; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D007108:Immune Tolerance / Q000187:drug effects*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008970:Molecular Weight; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D006820:Hyaluronic Acid