Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 44, Issue 10, Pages 3026-3044Publisher
WILEY
DOI: 10.1002/eji.201444694
Keywords
Autoimmunity; Experimental autoimmune encephalomyelitis/multiple sclerosis; Heat shock protein; Neuroimmunology; Tolerance/Suppression
Categories
Funding
- Polish Ministry of Science [N N401 027836]
- Polpharma Science Foundation [1/25/IX/10, 421/N-COST/2009/0, UMO-2012/04/A/NZ6/00423]
- NMSS RG [1001-K-11]
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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 (HINT1(38-57)/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 HINT1(38-57)/Hsp70 prevented the development of EAE, suppressed PLP139-151-induced T-cell proliferation, and blocked secretion of IL-17. HINT1(38-57)/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 HINT1(38-57)/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 HINT1(38-57)/Hsp70 stimulation, expression of DAP10 and DAP12 was significantly increased in NK cells. Thus, we have shown that the HINT1(38-57)/Hsp70 complex affects NK-cell function by enhancing NK-cell-dependent immunoregulation in the EAE model of autoimmune demyelination.
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