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

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

Published in Volume 116, Issue 7

J Clin Invest. 2006; 116(7):2022 doi:10.1172/JCI28423

Abstract | Full text | PDF

C D4⁺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⁺CD25^int and CD4⁺CD25^hi. 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.

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