Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling.
CD4+CD25+ Tregs regulate immunity, but little is known about their own regulation. We now report that the human 60-kDa heat shock protein (HSP60) acts as a costimulator of human Tregs, both CD4+CD25int and CD4+CD25hi. Treatment of Tregs with HSP60, or its peptide p277, before anti-CD3 activation significantly enhanced the ability of relatively low concentrations of the Tregs to downregulate CD4+CD25- or CD8+ target T cells, detected as inhibition of target T cell proliferation and IFN-gamma and TNF-alpha secretion. The enhancing effects of HSP60 costimulation on Tregs involved innate signaling via TLR2, led to activation of PKC, PI3K, and p38, and were further enhanced by inhibition of ERK. HSP60-treated Tregs suppressed target T cells both by cell-to-cell contact and by secretion of TGF-beta and IL-10. In addition, the expression of ERK, NF-kappaB, and T-bet by downregulated target T cells was inhibited. Thus, HSP60, a self-molecule, can downregulate adaptive immune responses by upregulating Tregs innately through TLR2 signaling.
Zanin-Zhorov
Alexandra
A
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Cahalon
Liora
L
Tal
Guy
G
Margalit
Raanan
R
Lider
Ofer
O
Cohen
Irun R
IR
D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020825:T-Box Domain Proteins; D016176:T-Lymphocyte Subsets / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000098815:T-bet Transcription Factor
D017252:CD3 Complex; D018834:Chaperonin 60; D016328:NF-kappa B; D015375:Receptors, Interleukin-2; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D051418:Focal Adhesion Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases