The Journal of Experimental Medicine
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Published 2 December 2002. doi:10.1084/jem.20020797
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© Rockefeller University Press, 0022-1007/2002/12/1403/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 11, December 2, 2002 1403-1414

A Signal Peptide Derived from hsp60 Binds HLA-E and Interferes with CD94/NKG2A Recognition

Jakob Michaëlsson1, Cristina Teixeira de Matos1, Adnane Achour1, Lewis L. Lanier2, Klas Kärre1 and Kalle Söderström1

1 Microbiology and Tumor Biology Center, Karolinska Institutet, 171 77 Stockholm, Sweden
2 Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94143

Address correspondence to Kalle Söderström, MTC, Karolinska Institutet, Box 280, 171 77 Stockholm, Sweden. Phone: 46-8-7286769; Fax: 46-8-304276; E-mail: kalle.soderstrom{at}mtc.ki.se

Human histocompatibility leukocyte antigen (HLA)-E is a nonclassical major histocompatibility complex (MHC) class I molecule which presents a restricted set of nonameric peptides, derived mainly from the signal sequence of other MHC class I molecules. It interacts with CD94/NKG2 receptors expressed on the surface of natural killer (NK) cells and T cell subsets. Here we demonstrate that HLA-E also presents a peptide derived from the leader sequence of human heat shock protein 60 (hsp60). This peptide gains access to HLA-E intracellularly, resulting in up-regulated HLA-E/hsp60 signal peptide cell-surface levels on stressed cells. Notably, HLA-E molecules in complex with the hsp60 signal peptide are no longer recognized by CD94/NKG2A inhibitory receptors. Thus, during cellular stress an increased proportion of HLA-E molecules may bind the nonprotective hsp60 signal peptide, leading to a reduced capacity to inhibit a major NK cell population. Such stress induced peptide interference would gradually uncouple CD94/NKG2A inhibitory recognition and provide a mechanism for NK cells to detect stressed cells in a peptide-dependent manner.

Key Words: CD94/NKG2 • MHC class I • cellular stress • peptide interference • hsp60


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