Edited by Marco Colonna, Washington University, and accepted by Editorial Board Member T. W. Mak August 29, 2018 (received for review December 23, 2017)
Finding that “innate” natural killer cells possessed T cell-like immune memory was an unprecedented discovery that rocked our understanding of the divide between innate and adaptive immunity. In this report we demonstrate that Ly49 receptors on natural killer cells, which engage the class I antigen-presenting platform on target cells, are critical components of adaptive natural killer cell memory. We also demonstrate the clinical potential of natural killer cell memory, using it to mediate a cancer vaccine against melanoma. These findings offer insights into how adaptive natural killer cell memory might function and what clinical applications this mysterious immune response might have.
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 contributions: A.W., M.M.A.R., and A.P.M. designed research; A.W., A.B.M., M.S., M.M.T., and M.M.A.R. performed research; A.B.M. and S.S. contributed new reagents/analytic tools; A.W., M.S., S.S., and A.P.M. analyzed data; and A.W., M.M.A.R., and A.P.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. M.C. is a guest editor invited by the Editorial Board.
See Commentary on page 11357.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1722374115/-/DCSupplemental.
Published under the PNAS license.
