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 10

Schematic diagram of the innate effects of HSP60 on Treg function.

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Schematic diagram of the innate effects of HSP60 on Treg function. The e...
The exposure of Tregs to HSP60 via innate TLR2 signaling amplifies their response to TCR-dependent (anti-CD3) stimulation, reflected by upregulation of AKT, Pyk2, and p38 and downregulation of ERK. These innate effects of HSP60 signaling amplify IL-10, TGF-β, and contact-dependent Treg suppressor mechanisms that impinge on TCR-activated CD4+CD25– T cells to downregulate ERK, NF-κB, and T-bet, leading, in turn, to downregulated proliferation and secretion of the proinflammatory cytokines IFN-γ and TNF-α and to upregulation of IL-10 secretion.