T cells respond to heat shock protein 60 via TLR2: activation of adhesion and inhibition of chemokine receptors.
Soluble 60 kDa heat shock protein (HSP60) activates macrophages via TLR4. We now report that soluble HSP60 activates T cells via the innate receptor TLR2. HSP60 activated T cell adhesion to fibronectin to a degree similar to other activators: IL-2, SDF-1alpha, and RANTES. T cell type and state of activation was important; nonactivated CD45RA+ and IL-2-activated CD45RO+ T cells responded optimally (1 h) at low concentrations (0.1-1 ng/ml), but nonactivated CD45RO+ T cells required higher concentrations (approximately 1 microg/ml) of HSP60. T cell HSP60 signaling was inhibited specifically by monoclonal antibodies (mAb) to TLR2 but not by a mAb to TLR4. Indeed, T cells from mice with mutated TLR4 could still respond to HSP60, whereas Chinese hamster T cells with mutated TLR2 did not respond. The human T cell response to soluble HSP60 depended on phosphatidylinositol 3-kinase and protein kinase C signaling and involved the phosphorylation of Pyk-2. Soluble HSP60 also inhibited actin polymerization and T cell chemotaxis through extracellular matrix-like gels toward the chemokines SDF-1alpha (CXCL12) or ELC (CCL19). Exposure to HSP60 for longer times (18 h) down-regulated chemokine receptor expression: CXCR4 and CCR7. These results suggest that soluble HSP60, through TLR2-dependent interactions, can regulate T cell behavior in inflammation.
Zanin-Zhorov
Alexandra
A
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. irun.cohen@weizmann.ac.il
Nussbaum
Gabriel
G
Franitza
Susanne
S
Cohen
Irun R
IR
Lider
Ofer
O
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006224:Cricetinae; D005353:Fibronectins; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018448:Models, Immunological; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
C515370:CCR7 protein, human; C515371:Ccr7 protein, mouse; D018834:Chaperonin 60; D005353:Fibronectins; D019012:Integrin beta1; D008562:Membrane Glycoproteins; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors