Abstract
Human CD4+CD25+FoxP3+ T regulatory cells (Tregs) control effector T cells and play a central role in peripheral tolerance and immune homeostasis. Heat shock protein 70 (HSP70) is a major immunomodulatory molecule, but its effect on the functions of Tregs is not well understood. To investigate target-dependent and –independent Treg functions, we studied cytokine expression, regulation of proliferation and cytotoxicity after exposure of Tregs to HSP70. HSP70-treated Tregs significantly inhibited proliferation of CD4+CD25− target cells and downregulated the secretion of the proinflammatory cytokines IFN-γ and TNF-α. By contrast, HSP70 increased the secretion of Treg suppressor cytokines IL-10 and TGF-β. Treatment with HSP70 enhanced the cytotoxic properties of Tregs only to a minor extent (4-fold), but led to stronger responses in CD4+CD25− cells (42-fold). HSP70-induced modulation of T-cell responses was further enhanced by combined treatment with HSP70 plus IL-2. Treatment of Tregs with HSP70 led to phosphorylation of PI3K/AKT and the MAPKs JNK and p38, but not that of ERK1/2. Exposure of Tregs to specific inhibitors of PI3K/AKT and the MAPKs JNK and p38 reduced the immunosuppressive function of HSP70-treated Tregs as indicated by the modified secretion of specific target cell (IFN-γ, TNF-α) and suppressor cytokines (IL-10, TGF-β). Taken together, the data show that HSP70 enhances the suppressive capacity of Tregs to neutralize target immune cells. Thus HSP70-enhanced suppression of Tregs may prevent exaggerated immune responses and may play a major role in maintaining immune homeostasis.
Highlights
Heat shock proteins (HSPs) are a highly conserved group of cytoprotective proteins which are typically up-regulated in response to various stress stimuli
We demonstrate that heat shock protein 70 (HSP70) and in particular the combination of HSP70 plus IL-2 enhances the capacity of T regulatory cells (Tregs) to increase the secretion levels of the immunosuppressive cytokines IL-10, TGF-b, and to decrease the activity CD4+CD252 target cells compared to untreated Tregs
Ki-67 expression was significantly higher in CD4+CD25+ T cells treated with HSP70 alone or in combination with IL-2 compared to either untreated cells or cells treated with IL-2 alone
Summary
Heat shock proteins (HSPs) are a highly conserved group of cytoprotective proteins which are typically up-regulated in response to various stress stimuli. HSPs have been identified in a wide variety of prokaryotic and eukaryotic cells They play an important role as intracellular molecular chaperones that prevent the aggregation and folding of proteins [1,2]. HSPs can further act at multiple points in apoptotic pathways to ensure that stressinduced damage does not inappropriately trigger cell death [3,4]. Knowledge of their immunological functions emerged with the observation that HSP70, HSP90, gp, calreticulin, HSP110 and GRP170 isolated from tumor cells can initiate adoptive, tumorspecific T-cell responses and protective immunity, whereas those from healthy cells do not [5,6]. Human heat shock protein 70 (HSP70) has potent immunomodulatory properties and has been shown to regulate the activity of T cells [7]
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