Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? Can Natural Killer and CD8 T Cells Switch Jobs? Christine A. Biron1 and Marcus Altfeld2 1Department of Molecular Microbiology and Immunology, The Division of Biology and Medicine, and The Warren Alpert Medical School, Brown University, Providence, Rhode Island 02903 2Institute of Immunology, University Medical Center Hamburg-Eppendorf; and Department of Virus Immunology, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany Correspondence: [email protected] Natural killer (NK) cells are components of innate immunity mediating defense at early times after viral infections. Their cytokine production and cell-mediated cytotoxicity functions overlap those of CD8 T cells elicited later during primary adaptive immune responses, but the populations are distinguished by their basal states and activating receptors as well as the kinetics of their responses. Demonstration of long-lived NK cells has led to speculation on the potential for inducing these to contribute to immunological memory. Conversely, activated CD8 T cells can acquire responses to innate cytokines and, as a result, have the potential to contribute to innate immunity. These observations beg the question: what is required to be a player in innate and adaptive immunity? GREAT DEBATES What are the most interesting topics likely to come up over dinner or drinks with your colleagues? Or, more importantly, what are the topics that don’t come up because they are a little too controversial? In Immune Memory and Vaccines: Great Debates, Editors Rafi Ahmed and Shane Crotty have put together a collection of articles on such ques- tions, written by thought leaders in these fields, with the freedom to talk about the issues as they see fit. This short, innovative format aims to bring a fresh perspective by encouraging authors to be opinionated, focus on what is most interesting and current, and avoid restating introductory material covered in many other reviews. The Editors posed 13 interesting questions critical for our understanding of vaccines and immune memory to a broad group of experts in the field. In each case, several different perspectives are provided. Note that while each author knew that there were additional scientists addressing the same question, they did not know who these authors were, which ensured the independence of the opinions and perspectives expressed in each article. Our hope is that readers enjoy these articles and that they trigger many more conversations on these important topics. Editors: Shane Crotty and Rafi Ahmed Additional Perspectives on Immune Memory and Vaccines: Great Debates available at www.cshperspectives.org Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a029892 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a029892 1 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press C.A. Biron and M. Altfeld ore than a hundred years of research led to cells in innate immunity. Questions of what it Mcharacterization of two major arms of the takes to be part of innate or adaptive immunity immune system: innate and adaptive. “Adaptive arise from this information. How did NK cells immunity” is defined as antigen-specific, slow get to first participate in innate immunity? What to develop during primary exposure, and re- will it take to get them to be important memory sponsible for long-lived immunity with height- cells? Can they compete with memory T cells to ened recall responses after secondary exposure. promote defense upon secondary exposures? It is known to be important for immunity in- Are they fit for the long haul after induction by duced by vaccination. Its antigen specificity is a vaccination? How often are the required ligand result of rearranging genes to express highly combinations for NK cell–activating receptors diverse antigen-specific receptors on a small expressed on infected target cells? The answers proportion of cells. Adaptive T-cell receptors to these questions may change the understand- recognize determinants of self-molecules mod- ing of innate and adaptive immunity with con- ified as a result of infection. In contrast, “innate sequences for approaches to vaccination. immunity” has been defined as depending on germline gene-encoded receptors, being present at all times, and functioning during early pri- RECEPTOR SPECIFICITY mary infections but not increasing after repeat- ed exposure. Innate receptor–ligand pairs are NK cells develop in the absence of adaptive im- more diverse and act to sense changes in the munity and are primed to contribute to innate expression of ligands as a result of infection or immunity. During first infections, they play im- stress. These descriptions of innate and adaptive portant roles in mediating defense early and de- immunity have been traditionally accepted in livering immunoregulatory functions at times assigning immune components to either arm, preceding the development of adaptive immu- and largely accommodate the evidence derived nity (Biron et al. 1999; Jost and Altfeld 2013; under immune-competent conditions. Natural Waggoner et al. 2016). Their effector functions, killer (NK) and CD8 T cells are, respectively, however, largely overlap those mediated by the constituents of innate and adaptive immunity. CD8 T cell stimulated at later times, that is, kill- Although they mediate overlapping effector ing of cells and production of cytokines such as functions, that is, cytotoxicity and producing IFN-γ. The two responses appear to be coordi- cytokines such as interferon γ (IFN-γ), they nated such that NK cell activation and function are stimulated to proliferation and mediate tar- occur early but wane as adaptive immunity is get cell lysis by different receptor–ligand pairs. escalating (Biron et al. 1999; Alter et al. 2007). They are also induced at different times after The early NK cell responses include those in- primary infections, with CD8 T cells clearly duced by elicited innate cytokines and those important for long-lived immunity to viral stimulated through activating receptors (Dokun infections. et al. 2001). The activating receptors can pro- Despite the justification for assigning the mote elevated NK cell expansion and cell-medi- immune functions as innate or adaptive, there ated cytotoxicity. Stimulation of NK cells by in- are a number of reported observations that blur nate cytokines leads to their production of the borders of these classifications. Included cytokines and has been studied under a variety among these are long-lived NK cells with a pro- of conditions. There are associations between posed potential to mediate adaptive-like immu- particular NK-activating receptors and viral in- nity and, conversely, elicited CD8 T cells with fections, including the recently described inter- the ability to respond to innate cytokines in a action between KIR3DS1 and HLA-F (Garcia- manner similar to that of NK cells. Thus, these Beltran et al. 2016); for the most part, however, reports suggest that NK cells may be players in the activating receptor–ligand pairs promoting adaptive immunity and that pools of memory resistance to infection are still poorly under- CD8 T cells can replace requirements for NK stood (Vidal et al. 2011; Jost and Altfeld 2013). 2 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a029892 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? The NK- and T-cell-activating receptors use murine NK cells, induced by sensitizing deter- overlapping signaling pathways (MacFarlane minants and having the ability to deliver antivi- and Campbell 2006), but are set up to recognize ral defense, were identified in two different sys- different types of changes on target cells. The tems. The first system used exposure to haptens T-cell receptors (TCRs) for antigens are products and vaccination with viral antigens, without in- of rearranged genes with one ligand specificity fection, to stimulate the NK cell populations per cell and, in the case of CD8 T cells, recogniz- (O’Leary et al. 2006; Paust et al. 2010a). After ing major histocompatibility class 1 (MHC1) isolation and transfer to naïve immunodeficient molecules presenting microbial peptides as li- recipients, the elicited NK cells were, respective- gands. NK cells, however, have receptors that ly, able to deliver hapten-specific contact sensi- are products of germline genes. Although there tivity or enhanced specific resistance against in- are finite numbers of these, their numbers are fection with viruses having the antigens used for high and unusually diverse. In addition to other sensitization. In the case of the viral challenges, genes, there are two major clusters for NK the agents used were vesicular stomatitis and cell receptors, the natural killer gene complex influenza viruses. The cell recipient mice were (NKGC) and the leukocyte receptor gene com- T-cell-deficient and in some cases T- and NK- plex (LRGC). The killer-cell immunoglobulin- cell-deficient, resulting in limited competition like receptor (KIR) family, included in the sec- from other cell populations. The second ap- ond complex, functions in primates.