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Is There Memory and Can It Be Harnessed by ?

Can Natural Killer and CD8 T Cells Switch Jobs?

Christine A. Biron1 and Marcus Altfeld2

1Department of Molecular Microbiology and , The Division of 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 Immunology, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany Correspondence: [email protected]

Natural killer (NK) cells are components of innate mediating defense at early times after viral . Their production and cell-mediated 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 . Conversely, activated CD8 T cells can acquire responses to innate 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

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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 : innate and adaptive. “Adaptive arise from this information. How did NK cells immunity” is defined as -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 . 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- 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- . 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 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 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 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).

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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 T-cell receptors (TCRs) for 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 -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 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. The C-type proach identified expansion of an NK cell subset -like family in the NKGC includes the with an activating receptor for a specific viral antigen 49 () receptors func- protein expressed on cells infected with murine tioning in rodents (Paust et al. 2010b; Vidal cytomegalovirus (MCMV) (Sun et al. 2009). et al. 2011). These genes are highly polygeneic This activating receptor, Ly49H, and its ligand, and polymorphic (Parham 2008). Many of the the m157 MCMV protein product, present an ligands recognized by their products are other unusual situation with direct recognition of a cellular proteins without infection-induced struc- viral protein product by an activating NK cell tural alterations. There are examples, however, receptor. Here again, the studies evaluating the with both the human KIR and mouse Ly49 recep- adaptive phenotype of these cell populations de- tors, of binding to MHC1 molecules modulated pended on conditions under which there were by infection-induced antigens (Kielczewska et al. no memory T cells and, in fact, no basal Ly4H 2009; Vidal et al. 2011; Fadda et al. 2012). Related NK cells. As a result, the “memory” NK cells also NK inhibitory receptors are in place to identify had an advantage in this system. To summarize, “normal” conditions. NK cells stochastically there are still many unresolved issues about how express receptor combinations on their cell sur- fit memory NK cells are in the context of com- faces. The net of exposure to ligands for the posite immune responses. activating versus those for inhibitory receptors Other reports showed that human NK cells, regulates the stimulatory signals to NK cells. in individuals with ongoing or previous viral Thus, NK cells have the potential to recognize infections, can have significant changes in their a broad range of changes that CD8 T cells do not, subset distribution (Cerwenka and Lanier 2016). but the ligands also have additional layers of reg- This was originally observed for human cyto- ulation to circumvent before their activating re- megalovirus infection (HCMV) (Guma et al. ceptor-dependent responses can be stimulated. 2004). Here, the subset of NK cells expressing the NK-activating receptor NKG2C, that is, NKG2Cpos, are expanded in human HCMV se- NK CELL SUBSET EXPANSION ropositive individuals, and increased after trans- AND FUNCTIONAL MEMORY plantation in response to recipient cytomegalo- Surprising observations have led to speculation virus (CMV) (Foley et al. 2012). Recent studies about the potential for eliciting memory NK have shown that these expanded NK cells have cells to promote lasting immunity. Long-lived undergone epigenetic remodeling of the IFN-

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C.A. Biron and M. Altfeld

γ conserved noncoding sequence (CNS) 1 paredness to experience innate cytokines. The (Luetke-Eversloh et al. 2014), similar to what composition of innate cytokine responses to in- has been previously described for memory T fections can vary from one virus to another, but cells. Persisting expansion of NKG2Cpos NK they generally include the type 1 IFNs αβ, inter- cells has also been observed in other viral infec- leukin (IL)-15, and IL-18. Some, but not all, tions, such as hantavirus or C virus viruses also elicit the proinflammatory cytokine infection (Golden-Mason et al. 2008; Oliviero cascade, including IL-12, tumor factor, et al. 2009; Björkström et al. 2011). The viral and IL-6 production. NK cells are ready to re- stimulus for expansion under the different in- spond to innate cytokines with IFN-γ produc- fection conditions, however, is unclear because tion because, unlike resting T cells, they express it preferentially occurs in the context of CMV high levels of signal transducers and activators coinfection. Changes in the NK cell expressing of transcription 4 (STAT4) and are primed to ex- other receptors have also been described for oth- press the IL-12 receptor (IL-12R) (Nguyen et al. er viral infections. For example, specific KIRpos 2000; Miyagi et al. 2007; Mack et al. 2011). NK cell populations have been reported to ex- The IL-12R is a potent, whereas the type 1 IFN pand during primary human immunodeficien- receptor (IFNR) is a conditional, activator of cy virus (HIV)-1 infection, with a preferential STAT4. The basal availability of the receptors expansion of “licensed” NK cell populations ex- and high STAT4 levels in NK cells equip them pressing inhibitory KIRs (Korner et al. 2014). to respond to these cytokines with STAT4 ac- The precise mechanisms that lead to the expan- tivation and downstream expression of the sion of specific human NK cell subpopulations STAT4-dependent gene target IFN-γ. The pres- during viral infections remain incompletely un- ence ofIL-18 is astrong cofactorfor the response. derstood, and the relative importance of these Thus, NK cells are a first source of IFN-γ during expanded NK cells in mediating protection innate immune responses to infection. against the human viral infections remains to This “primed” state for IFN-γ production, be tested. however, is something T-cell populations can Work in nonhuman primates has begun to acquire. As CD8 T cells are stimulated through assess the longevity of NK cells expanded after their TCRs during viral infections, they expand vaccination (Reeves et al. 2015). Splenic and he- and are induced to express higher STAT4 levels patic NK cells from rhesus macaques receiving and to respond to IL-12 and type 1 IFNs with an experimental HIV-1 vaccine killed antigen- STAT4 activation and STAT4-dependent re- matched but not antigen-mismatched targets up sponses, including IFN-γ production (Gil et al. to 5 years after vaccination, indicating that du- 2012). The elevated STAT4 levels and innate rable antigen-specific NK cell memory can be cytokine responsiveness is maintained by pop- induced in primates. However, the NK cell re- ulations of memory CD8 T cells such that they ceptors that mediate such antigen-specific can be contributors to early “innate” IFN-γ pro- responses are unknown. Moreover, as these duction following exposure to an unrelated viral studies were conducted in the context of anti- infection inducing the innate cytokines (Suarez- gen-specific induction, it remains Ramirez et al. 2014). In particular, murine possible that long-term persisting memory T memory CD8 T cells specific for the lympho- helper cells might provide an immunological cytic choriomeningitis virus (LCMV) had environment enabling persistence or reactiva- STAT4-dependent IFN-γ responses to innate tion of NK cell subpopulations. cytokines induced at early times after MCMV infection. In contrast to their IFN-γ response, their proliferative responses were dependent CYTOKINE STIMULATION OF NK AND CD8 on the specific antigens for their TCRs. Other T CELLS reports have also shown antigen-independent In addition to differences in receptor usage, NK stimulation of memory CD8 T-cell IFN-γ pro- and CD8 T cells are different in their basal pre- duction (Soudja et al. 2012). These studies sug-

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Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination?

gest that the NK-cell uniqueness for providing there is a lack of knowledge about how often early responses to innate cytokines alone might ligands for NK-activating receptors are avail- be a temporary condition before the induction able to stimulate these populations in virus-in- of memory CD8 T-cell pools with their different fected cells during secondary stimulation, and activating receptor specificities. The relative im- how important they would be in the cauldron of portance of, or potential for, CD8 T cells to sub- virus-induced changes that can be detected by stitute for NK cells in providing innate IFN-γ, T cells. however, remains to be determined, and might Another intriguing question, however, is depend on the virus and/or the specific tissue what did it take for NK cells to become part of environment. innate immunity. Their characteristic of basal preparedness to response to innate cytokines is a distinguishing characteristic in “naïve” condi- ACTIVATION STATES AND CELL tions, but something that CD8 T cells develop MAINTENANCE after stimulations through their TCRs. This sug- Although NK cells were originally thought to be gests that the basal NK cell state may have been end-stage cells, they were shown to be capable derived by stimulation of their activating recep- of early cytokine-driven division. Eventually, tors before any exogenous viral challenge. The conditions inducing their proliferation and ex- candidate activating receptors and indeed the pansion through activating receptors were iden- candidate ligands for such events remain un- tified. Before the reports of changing subset dis- known, but the purposeful stimulation of basal tribution of NK cells during certain viral NK cells to produce memory cells is not analo- infections, diminishing NK cell presence had gous to the generation of memory T cells from been reported. Some of the questions of in- their truly resting states during primary antigen creasing or decreasing numbers were reconciled exposures. It might be compared with inducing when it was shown that NK cells dramatically memory T cells from cytotoxic T waned during unrelenting MCMV infections (CTLs). These fully developed effector T cells unless they had the specific Ly49H-activating are not hardy in terms of longevity. Taken to- receptor for the MCMV m157 antigen (Lee gether, the characteristics of NK and CD8 T cells et al. 2009). In contrast, the Ly49H subset un- suggest that basal NK cells seen in the periphery derwent profound expansion. Thus, “selection” might have undergone stimulation through an of the NK cells recognizing a virus-induced de- activating receptor at some point in their devel- terminant to change the proportions and num- opment, to result in populations that are ready bers of the subset is reminiscent of the mainte- to respond to innate cytokines. It is this “prim- nance of pools of memory T cells over time. ing” that enables them to contribute to innate Because NK and CD8 T cells can both be stim- immunity. However, it might provide unique ulated through their activating receptors, a challenges for attempts to induce subsets with common potential for inducing pools of these specific activating receptors into memory pools. cells to act during future challenges seems po- tentially possible. Their activating receptors CONCLUDING REMARKS would be stimulated to induce their prolifera- tion and their delivery of target cell killing. Surprising discoveries have driven dramatic However, NK cells have the distinguishing shifts in the understanding of innate and adap- characteristic of expressing opposing inhibitory tive immunity. At this time, there is excitement receptors. Thus, there are questions about how about the potential of inducing “memory” NK long a pool of NK cells enriched in a subset of cells by vaccination to help defend against chal- activating receptors would be maintained in the lenging viral infections. Given that “memory” face of normal cell ligands for the inhibitory NK cells did not confound the early character- receptors, and what it would take to access ization of memory T cells, it is difficult to expect them during secondary exposures. Moreover, that they will be major contributors. A caveat,

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C.A. Biron and M. Altfeld

however, might be that the systems used to iden- shown in Figure 1. As traditionally character- tify memory T cells were all predisposed to in- ized, NK cells participate in innate immunity ducing potent CD8 T-cell-mediated antiviral ef- after primary infections that have a delayed spe- fects. Conditions that do not fit this description, cific CD8 T-cell response to virus-induced anti- could present a setting for “memory” NK cells to gens (Fig. 1A). If a subset of NK cells were se- emerge in heightened defense during secondary lected through activating receptor stimulation as infections. a result of infection-induced changes in expres- Models for combinations of NK and T-cell sion of their ligands, these cells, along with players in primary and secondary infections are memory CD8 T cells, might contribute to

A Overall Innate

Primary Secondary Adaptive infection infection

NK

T

B or C Magnitude of response Unrelated Unrelated infection infection overlapping NK ligands

Time

Figure 1. Can natural killer (NK) and CD8 T cells both promote innate and adaptive immunity? (A) During primary viral infections, NK cells (light blue) contribute to innate immunity by making interferon γ (IFN-γ)in response to innate cytokines and under certain conditions, killing virus-infected target cells recognized by their activating receptors. Adaptive responses, including those delivered by CD8 T cells (dark blue/purple), have delayed kinetics but clear viral infections and result in memory T cells. Recent work has shown that stimulated CD8 T cells and the resulting memory cells can contribute to innate IFN-γ production on secondary exposure, but this response is limited because of the rapid recall of antigen-specific memory T cells. (B) In the case of an unrelated infection, both NK and memory T cells can contribute to early IFN-γ production, but clearance is primarily dependent on a new primary T-cell response to different antigens. (C) The interesting possibility of having NK cells contribute to memory protection has recently developed. These cells would have to be stimulated through their activating receptors for expansion by ligands commonly expressed on infected cells to provide a broad new line of defense. This last situation has yet to be identified.

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Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination?

heightened defense during secondary infection. Björkström NK, Lindgren T, Stoltz M, Fauriat C, Braun M, In the settings used to characterize immunity Evander M, Michaelsson J, Malmberg KJ, Klingstrom J, Ahlm C, et al. 2011. Rapid expansion and long-term per- thus far, however, memory CD8 T cells have sistence of elevated NK cell numbers in humans infected been sufficiently dominant to “mask” any mem- with hantavirus. J Exp Med 208: 13–21. ory NK cell contribution. Both NK and memory Cerwenka A, Lanier LL. 2016. Natural killer cell memory in infection, inflammation and . Nat Rev Immunol 16: CD8 T cells would be available to contribute to 112–123. early innate cytokine responses following sec- Dokun AO, Kim S, Smith HR, Kang HS, Chu DT, Yokoyama ondary infections, but this response would be WM. 2001. Specific and nonspecific NK cell activation of limited duration as adaptive recall responses during virus infection. Nat Immunol 2: 951–956. Fadda L, Korner C, Kumar S, van Teijlingen NH, Piechocka- quickly clear the virus and, consequently, induc- Ã Trocha A, Carrington M, Altfeld M. 2012. HLA-Cw tion of innate cytokines. Both NK and memory 0102-restricted HIV-1 p24 variants can modulate CD8 T cells are available to contribute to innate the binding of the inhibitory KIR2DL2 receptor and pri- 8: cytokine responses following infection with an mary NK cell function. PLoS Pathog e1002805. Foley B, Cooley S, Verneris MR, Curtsinger J, Luo X, Waller unrelated agent, but under these conditions a EK, Anasetti C, Weisdorf D, Miller JS. 2012. Human cy- new set of antigen-specific CD8 T cells would tomegalovirus (CMV)-induced memory-like NKG2C+ need to be induced to fight off the virus (Fig. 1B). NK cells are transplantable and expand in vivo in re- “ ” sponse to recipient CMV antigen. J Immunol 189: Is there a possibility that a pool of memory NK 5082–5088. cells, elicited through an activating receptor ca- Garcia-Beltran WF, Holzemer A, Martrus G, Chung AW, pable of recognizing ligands commonly ex- Pacheco Y, Simoneau CR, Rucevic M, Lamothe-Molina pressed on cells challenged by different viruses, PA, Pertel T, Kim TE, et al. 2016. Open conformers of HLA-F are high-affinity ligands of the activating NK-cell could provide memory defense independent of receptor KIR3DS1. Nat Immunol 17: 1067–1074. memory CD8 T cells? (Fig. 1C) This has yet to be Gil MP, Ploquin MJ, Watford WT, Lee SH, Kim K, Wang X, shown. In the end, keys to accessing NK cells for Kanno Y, O’Shea JJ, Biron CA. 2012. Regulating type 1 long-term immunity likely lie in understanding: IFN effects in CD8 T cells during viral infections: Chang- fi “ ” ing STAT4 and STAT1 expression for function. the antigen-speci city of memory NK cells, 120: 3718–3728. the basal conditions influencing their potential Golden-Mason L, Madrigal-Estebas L, McGrath E, Conroy for long-term maintenance, and how the ligands MJ, Ryan EJ, Hegarty JE, O’Farrelly C, Doherty DG. 2008. for their activating and inhibitory receptors are Altered natural killer cell subset distributions in resolved and persistent hepatitis C virus infection following single regulated to promote their maintenance and re- source exposure. Gut 57: 1121–1128. activation. The next period of study promises to Guma M, Angulo A, Vilches C, Gomez-Lozano N, Malats N, be enlightening. Lopez-Botet M. 2004. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 104: 3664–3671. Jost S, Altfeld M. 2013. Control of human viral infections by 31: – ACKNOWLEDGMENTS natural killer cells. Annu Rev Immunol 163 194. Kielczewska A, Pyzik M, Sun T, Krmpotic A, Lodoen MB, The authors thank the members of their labora- Munks MW, Babic M, Hill AB, Koszinowski UH, Jonjic S, tories, past and present, as well as the many et al. 2009. Ly49P recognition of cytomegalovirus-infect- ed cells expressing H2-Dk and CMV-encoded m04 cor- researchers who contributed to the work sum- relates with the NK cell antiviral response. J Exp Med 206: marized here. 515–523. Korner C, Granoff ME, Amero MA, Sirignano MN, Vaidya SA, Jost S, Allen TM, Rosenberg ES, Altfeld M. 2014. Increased frequency and function of KIR2DL1-3+ NK REFERENCES cells in primary HIV-1 infection are determined by HLA-C group haplotypes. Eur J Immunol 44: 2938– Alter G, Teigen N, Ahern R, Streeck H, Meier A, Rosenberg 2948. ES, Altfeld M. 2007. of innate and adaptive Lee SH, Kim KS, Fodil-Cornu N, Vidal SM, Biron CA. effector cell functions during acute HIV-1 infection. J 2009. Activating receptors promote NK cell expansion Infect Dis 195: 1452–1460. for maintenance, IL-10 production, and CD8 T cell 206: Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Ma- regulation during viral infection. J Exp Med – ther TP. 1999. Natural killer cells in antiviral defense: 2235 2251. Function and regulation by innate cytokines. Annu Rev Luetke-Eversloh M, Hammer Q, Durek P, Nordstrom K, Immunol 17: 189–220. Gasparoni G, Pink M, Hamann A, Walter J, Chang HD,

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Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination?: Can Natural Killer and CD8 T Cells Switch Jobs?

Christine A. Biron and Marcus Altfeld

Cold Spring Harb Perspect Biol 2018; doi: 10.1101/cshperspect.a029892 originally published online December 18, 2017

Subject Collection Immune Memory and Vaccines: Great Debates

Is There Natural Killer Cell Memory and Can It Be Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination?: Can Natural Killer Harnessed by Vaccination?: NK Cell Memory and and CD8 T Cells Switch Jobs? Strategies against Infectious Christine A. Biron and Marcus Altfeld Diseases and Cancer Joseph C. Sun and Lewis L. Lanier Is There Natural Killer Cell Memory and Can It Be Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination?: Vaccination Harnessed by Vaccination?: Natural Killer Cells in Strategies Based on NK Cell and ILC Memory Vaccination Megan A. Cooper, Todd A. Fehniger and Marco Harold R. Neely, Irina B. Mazo, Carmen Gerlach, et Colonna al. Is It Possible to Develop Cancer Vaccines to Is It Possible to Develop Cancer Vaccines to Neoantigens, What Are the Major Challenges, and Neoantigens, What Are the Major Challenges, and How Can These Be Overcome?: Neoantigens as How Can These Be Overcome?: Targeting the Vaccine Targets for Cancer Right Antigens in the Right Patients Haydn T. Kissick Stephen P. Schoenberger Is It Possible to Develop Cancer Vaccines to Which Dengue Vaccine Approach Is the Most Neoantigens, What Are the Major Challenges, and Promising, and Should We Be Concerned about How Can These Be Overcome?: Neoantigens: Enhanced Disease after Vaccination?: There Is Nothing New in Spite of the Name Only One True Winner Olivera J. Finn and Hans-Georg Rammensee Scott B. Halstead Which Dengue Vaccine Approach Is the Most Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Promising, and Should We Be Concerned about Enhanced Disease after Vaccination?: The Enhanced Disease after Vaccination?: Questions Challenges of a Dengue Vaccine Raised by the Development and Implementation Gavin Screaton and Juthathip Mongkolsapaya of Dengue Vaccines: Example of the Sanofi Pasteur Tetravalent Dengue Vaccine Bruno Guy

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Which Dengue Vaccine Approach Is the Most Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Promising, and Should We Be Concerned about Enhanced Disease after Vaccination?: The Path to Enhanced Disease after Vaccination?: The Risks a Dengue Vaccine: Learning from Human Natural of Incomplete Immunity to Dengue Virus Revealed Dengue Infection Studies and Vaccine Trials by Vaccination Aravinda M. de Silva and Eva Harris Stephen S. Whitehead and Kanta Subbarao Is It Possible to Develop a ''Universal'' Influenza Is It Possible to Develop a ''Universal'' Influenza Virus Vaccine?: Potential for a Universal Influenza Virus Vaccine?: Immunogenetic Considerations Vaccine Underlying B-Cell Biology in the Development of a James E. Crowe, Jr. Pan-Subtype Influenza A Vaccine Targeting the Hemagglutinin Stem Sarah F. Andrews, Barney S. Graham, John R. Mascola, et al. Is It Possible to Develop a ''Universal'' Influenza Is It Possible to Develop a ''Universal'' Influenza Virus Vaccine?: Outflanking Virus Vaccine?: Potential Target Antigens and Immunodominance on the Road to Universal Critical Aspects for a Universal Influenza Vaccine Influenza Vaccination Florian Krammer, Adolfo García-Sastre and Peter Davide Angeletti and Jonathan W. Yewdell Palese

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