Cutting edge: high molecular weight hyaluronan promotes the suppressive effects of CD4+CD25+ regulatory T cells.
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.
Bollyky
Paul L
PL
Benaroya Research Institute, Seattle, WA 98101, USA. pbollyky@benaroyaresearch.org
Lord
James D
JD
Masewicz
Susan A
SA
Evanko
Stephen P
SP
Buckner
Jane H
JH
Wight
Thomas N
TN
Nepom
Gerald T
GT
D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000276:immunology* / Q000378:metabolism*; D007113:Immunity, Innate / Q000502:physiology*; D007249:Inflammation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014158:Transcription, Genetic
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid