Unexpected role for granzyme K in CD56bright NK cell-mediated immunoregulation of multiple sclerosis

• Published in: The Journal of immunology (1950) Vol. 187; no. 2; pp. 781 - 790
• Main Authors: Jiang, Wenzheng, Chai, Noo Ri, Maric, Dragan, Bielekova, Bibiana
• Format: Journal Article
• Language: English
• Published: United States 15.07.2011
• Subjects: Adaptive Immunity; Antibodies, Blocking - therapeutic use; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; CD56 Antigen - biosynthesis; CD56 Antigen - physiology; Cell Death - genetics; Cell Death - immunology; Cell Line; Cell Line, Transformed; Coculture Techniques; Cytotoxicity, Immunologic; Daclizumab; Gene Silencing - immunology; Granzymes - antagonists & inhibitors; Granzymes - genetics; Granzymes - physiology; Humans; Immunoglobulin G - therapeutic use; Immunosuppressive Agents - therapeutic use; Killer Cells, Natural - enzymology; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Male; Middle Aged; Multiple Sclerosis - enzymology; Multiple Sclerosis - immunology; Multiple Sclerosis - therapy; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - pathology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1100789

Functional NK cell deficiencies are associated with autoimmune diseases, including multiple sclerosis. NK cells can promote or inhibit adaptive immunity via either cytokine production or cytotoxicity toward immature dendritic cells and activated T cells. In humans, this immunoregulatory role resides in the CD56(bright) NK cell subset, which is selectively expanded by daclizumab, a CD25-blocking Ab that suppresses multiple sclerosis-associated inflammation. The objective of this study was to investigate the molecular mechanisms underlying the cytotoxicity of NK cells toward activated T cells. We demonstrated that NK cells induce caspase-independent apoptosis that requires NK cell degranulation and causes mitochondrial dysfunction in activated T cells. Although both granzyme A and granzyme K (GrK) can mediate this form of apoptosis, quantitatively we observed preferential transfer of GrK to target cells. Consequently, gene silencing of GrK in the NK-92 cell line, which retains functional characteristics of CD56(bright) NK cells, profoundly inhibited the ability of NK-92 cells to kill activated syngeneic T cells. Finally, we demonstrated that daclizumab treatment significantly enhanced this newly defined mechanism of cytotoxicity by CD56(bright) NK cells. Our study describes the important physiological role that GrK plays in immunoregulation of adaptive immunity in humans and indicates that therapeutic exploitation of this pathway is beneficial in controlling autoimmunity.