Delving into the mechanism of the emerging observation that some NK cells exhibit “memory” for specific antigens, Wight et al. used Ly49 genetic manipulation and altered MHC epitope peptides in an ear swelling test in T and B cell-deficient Rag1-/- mice to demonstrate that Ly49 receptors on NK cells engage peptide:MHC in an antigen-specific manner. Immunization of T cell-deficient mice with either of two protein antigens resulted in protection of 50% of animals from challenge with cognate antigen-expressing tumors. Peptide vaccination was less effective but showed dramatic peptide-specific NK cell infiltration.
Adaptive natural killer (NK) cell memory represents a new frontier in immunology. Work over the last decade has discovered and confirmed the existence of NK cells with antigen-specific memories, which had previously been considered a unique property of T and B cells. These findings have shown that antigen-specific NK cells gain their specificity without the use of RAG proteins, representing a novel mechanism for generating antigen specificity, but the details of this mechanism have remained a mystery. We have discovered that members of the Ly49 family of surface receptors are critically involved in both the sensitization and the challenge phases of an NK cell memory response, as is antigen presentation from their binding partner, the class I MHC. Moreover, we demonstrate that the Ly49-interacting component of a presented antigen dictates the specificity of the NK cell memory response, implicating Ly49 receptors themselves in antigen-specific recognition. Finally, we demonstrate that adaptive NK cell memories can protect against an otherwise lethal melanoma without T cell or B cell support. These findings offer insight into the mechanism behind NK cell antigen specificity and demonstrate the clinical potential of this adaptive immune cell.
Author Info: (1) Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada. Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada. (2
Author Info: (1) Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada. Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada. (2) Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada. Laboratory Science, Taibah University, Medina 42353, Kingdom of Saudi Arabia. (3) Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada. (4) Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada. (5) Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada. Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada. (6) Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada. (7) Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada; Andrew.Makrigiannis@dal.ca. Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada.
