Journal Article

HSP70 Enhances Immunosuppressive Function of CD4+CD25+FoxP3+ T Regulatory Cells and Cytotoxicity in CD4+CD25− T Cells

Tischer, Sabine, Figueiredo, Constanca, Eiz-Vesper, Britta, Wachstein, Julian, Limbourg, Anne, Falk, Christine, Blasczyk, Rainer, Immenschuh, Stephan

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 1-Phosphatidylinositol 3-kinase / Adult / AKT protein / Antigens / Apoptosis - immunology / Autoimmune diseases / Biology / CD25 antigen / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - metabolism / Cell adhesion & migration / Cell proliferation / Cloning / Combined treatment / Cytokines / Cytotoxicity / Effector cells / Enzyme-Linked Immunosorbent Assay / Exposure / Female / Flow Cytometry / Fluorescent Antibody Technique / Forkhead Transcription Factors - metabolism / Foxp3 protein / Granzymes - secretion / Heat shock proteins / Homeostasis / HSP70 Heat-Shock Proteins - metabolism / Hsp70 protein / Humans / Immune response / Immune system / Immunological tolerance / Immunology / Immunomodulation / Immunoregulation / Immunosuppression / Immunosuppressive agents / Immunosuppressive Agents - pharmacology / Inflammation / Interferon / Interleukin 10 / Interleukin 2 / Interleukin-10 - metabolism / Interleukin-2 Receptor alpha Subunit - metabolism / JNK protein / Lymphocytes / Lymphocytes T / Male / MAP Kinase Kinase 4 - metabolism / Medical schools / Medicine / Middle Aged / p38 Mitogen-Activated Protein Kinases - metabolism / Phosphatidylinositol 3-Kinases - metabolism / Phosphorylation / Proto-Oncogene Proteins c-akt - metabolism / Signal transduction / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - metabolism / Toxicity / Transforming Growth Factor beta - metabolism / Tumor necrosis factor-α / γ-Interferon