title: HINT1 peptide/Hsp70 complex induces NK-cell-dependent immunoregulation in a model of autoimmune demyelination.
abstract: Heat shock proteins (Hsps) interact with the immune system and have been shown to contribute to immunoregulation. As efficient chaperones, Hsps bind many peptides and these complexes have many yet-to-be-clarified functions. We have shown that Hsp70 is complexed within the mouse CNS with peptide CLAFHDISPQAPTHFLVIPK derived from histidine triad nucleotide-binding protein-1 (HINT1₃₈₋₅₇/Hsp70). Only this complex, in contrast to other peptides complexed with Hsp70, was able to prevent experimental autoimmune encephalomyelitis (EAE) by induction of immunoregulatory mechanisms dependent on NK cells. Pretreatment of proteolipid protein peptide ₁₃₉₋₁₅₁(PLP₁₃₉₋₁₅₁) sensitized SJL/J mice with HINT1₃₈₋₅₇/Hsp70 prevented the development of EAE, suppressed PLP₁₃₉₋₁₅₁-induced T-cell proliferation, and blocked secretion of IL-17. HINT1₃₈₋₅₇ /Hsp70 stimulation of NK cells depended on synergistic activation of two NK-cell receptors, CD94 and NKG2D. NK cells with depleted CD94 or with blocked NKG2D did not inhibit PLP₁₃₉₋₁₅₁-induced spleen cell (SC) proliferation. The HINT1₃₈₋₅₇/Hsp70 complex enhanced surface expression of the NKG2D ligand-H60. Downstream signaling of CD94 and NKG2D converged at the adaptor proteins DAP10 and DAP12, and in response to HINT1₃₈₋₅₇ /Hsp70 stimulation, expression of DAP10 and DAP12 was significantly increased in NK cells. Thus, we have shown that the HINT1₃₈₋₅₇ /Hsp70 complex affects NK-cell function by enhancing NK-cell-dependent immunoregulation in the EAE model of autoimmune demyelination.
authors.affiliation: Department of Neurology, Medical University of Lodz, Lodz, Poland.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Galazka
authors.forename: Anna
authors.initials: A
authors.lastname: Jurewicz
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Domowicz
authors.forename: Barbara
authors.initials: B
authors.lastname: Cannella
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Raine
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Selmaj
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D018920:Coculture Techniques; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D013058:Mass Spectrometry; D051379:Mice; D009419:Nerve Tissue Proteins / Q000276:immunology*; D015213:Neuroimmunomodulation / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018840:HSP70 Heat-Shock Proteins; C489275:Hint1 protein, mouse; D009419:Nerve Tissue Proteins; D010455:Peptides
keywords: Autoimmunity; Experimental autoimmune encephalomyelitis/multiple sclerosis; Heat shock protein; Neuroimmunology; Tolerance/Suppression