Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling
Alexandra Zanin-Zhorov, … , Ofer Lider, Irun R. Cohen
Alexandra Zanin-Zhorov, … , Ofer Lider, Irun R. Cohen
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):2022-2032. https://doi.org/10.1172/JCI28423.
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Research Article Immunology

Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling

Abstract

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-γ and TNF-α 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-β and IL-10. In addition, the expression of ERK, NF-κB, 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.

Authors

Alexandra Zanin-Zhorov, Liora Cahalon, Guy Tal, Raanan Margalit, Ofer Lider, Irun R. Cohen

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Figure 9

Coculture of CD4+ CD25– T cells with HSP60-treated CD4+ CD25+ T cells downregulates ERK phosphorylation and inhibits nuclear translocation of NF-κB and T-bet expression in the CD4+ CD25– T cells.

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Coculture of CD4+ CD25– ...
CD4+CD25– T cells were labeled with CFSE, washed, and cocultured with HSP60-treated (1 ng/ml, 2 hours) CD4+CD25+ T cells (ratio 1:10) on anti-CD3 in serum-free medium for 6 hours. The CD4+CD25– T cells were reisolated by FACS sorting, and cell lysates of these cells were immunoblotted with antibodies: anti–phospho-ERK (p-ERK) and anti–total ERK (t-ERK) (A), anti–NF-κB or anti–lamin B (B), or anti–T-bet or anti–t-ERK (C). The blot of 1 experiment representative of 4 different donors is presented. The levels of ERK phosphorylation, NF-κB, and T-bet were estimated by densitometry, and the average percentage derived from 4 different donors is shown.