NK cells stroll down the memory lane

Antigen recognition, which leads to a stronger immune response upon re-challenge, has always been attributed to memory T and B cells. New evidence suggests that natural killer cells possess immunological memory providing enhanced protection to subsequent infections with the same pathogen. The crucial ability of our immune system to remember past encounters with a pathogen and elicit improved response to a secondary challenge provides long-term protection and makes vaccination possible. This immunological memory is the hallmark of adaptive responses mediated by T and B cells. Or is it? In the first February issue of Nature, Sun et al.1 challenge this dogma by showing that subsequent to infection with mouse cytomegalovirus (MCMV), a subset of natural killer (NK) cells develops into memory cells. Natural killer cells are cytotoxic lymphocytes of the innate immune system. They are potent effector cells that swiftly eliminate tumors and infected cells while providing signals that shape adaptive immune responses. Unlike other lymphocyte subsets, NK cells do not rearrange the genes that encode their receptors. Instead, they possess a complex array of germ-line encoded inhibitory and activating receptors that regulate their function. Further, on binding to self major histocompatibility complex molecules, they are actively inhibited from responding,2 rather than activated. Not too long ago NK cells were considered to lack any antigen specificity, and killing was thought to be a ‘default’ mechanism in the absence of inhibitory signals. In the recent years, our view of NK cell function has expanded largely based on experimental data from the model of MCMV infection. For instance, NK cell activating receptors can provide specific recognition of infected cells. The best characterized example is the Ly49H receptor, which does not recognize any self-antigen but rather binds to the MCMV-encoded m157 molecule.3 When an NK cell bearing Ly49H encounters an MCMV-infected cell, the receptor activates a signaling cascade to result in cytokine production, cell kill and, notably, clonal proliferation.4 Moreover, accumulating data indicate that NK cells have to be educated to acquire their functions.5, 6 One group suggested the existence of NK cell memory in a model of chemically-induced contact dermatitis in mice lacking T and B lymphocytes, the classical mediators of this disease. However, the mechanism of the recall response or a possible role for this NK memory population during infection was not known.7 Investigating NK cell memory during MCMV infection has several limitations. Immuno-deficient mice, a common model to track memory cells without the interference of other immune cells, cannot be used; without adaptive immunity, animals succumb to MCMV infection before one can trace the long-lived NK cells. Sun et al. overcame this problem with a clever experimental strategy. They used DAP12 deficient (DAP12−/−) mice as recipients in mixed bone-marrow and NK cell adoptive transfers. These mice lack Ly49H-mediated function but otherwise mount a normal immune response. Donor cells originated from wild-type mice expressing a distinctive lymphocyte marker, which allowed tracing Ly49H+ NK cells. Importantly, in this system only the donor's NK cells respond to a MCMV challenge, as DAP12−/− NK cells cannot recognize the infection (Figure 1a). In a series of elegant experiments, Sun et al. show that Ly49H+ NK cells can recapitulate the general features of memory cell generation. First, the proliferative potential of Ly49H+ NK cells during MCMV infection was explored. Thus, only the Ly49H+ NK cells from the wild-type bone-marrow donor were able to expand in response to MCMV infection. Importantly, the process was m157-restricted as no amplification was observed upon infection with a mutant virus lacking the Ly49H ligand. More dramatic amplification was shown when NK cells from wild-type mice were adoptively transferred into recipient MCMV-infected animals. By day 7, Ly49H+ NK cells multiplied 100-fold and became the predominant NK cell subset, falling to initial numbers at later time points (Figure 1b). Second, the authors detect the presence of Ly49H+ NK cells up to 70 days after transfer. The ability to recover donor cells that late is unexpected as the generally accepted half-life of mature NK cells is 7–10 days. When studying memory cells, the continuous presence of antigen is of prime importance. In the presence of permanent low-level stimulus, one could be following activated rather than memory NK cells. This may not be the case here as T cells from the recipient mice provide sterilizing immunity. Thus, the presence of m157-sensitized Ly49H+ NK cells more than 2 months after immunization could satisfy the definition of long-lived memory cells. Sun et al. went ahead to document that memory NK cells were not only functional ex-vivo but also had superior effector response compared with naïve NK cells. Therefore, Ly49H+ NK cells undergo both a phase of rapid and massive m157-specific proliferation, which is followed by a protracted phase of contraction and memory maintenance (Figures 1b and c). Third, to assess the recall response, the authors recovered m157-experienced long-lived Ly49H+ donor cells and transferred those into recipient adult mice, which were infected with MCMV. When the response of memory Ly49H+ NK cells was compared with that of the naïve NK cells, both populations had similar magnitude and kinetics of proliferation (Figures 1b and c). Moreover, newborn mice, upon adoptive transfer of the memory Ly49H+ NK cells and infection, were significantly more resistant than the controls, receiving naïve Ly49H+ NK cells. The study by Sun et al. shows that immunological memory is a function of NK cells. An important aspect of the experimental design is the development of memory NK cells in face of the intact lymphocyte compartment, not as a compensatory mechanism in the absence of adaptive immune response. Nevertheless, the specific role of memory Ly49H+ NK cells in a context of a fully mature immune system, especially during secondary infectious challenges, needs to be assessed. However, these data put in perspective the contribution of long-lived NK cells to the functions earlier attributed to memory T cells during infection. As well, hitherto puzzling results and failures in the efficacy of T cell-based vaccines should be re-examined. How general is this phenomenon likely to be? MCMV has been persistent through host's history and has been proposed to drive the evolution of mouse NK receptors and their ligands. Although there are many reports of NK cell-mediated immunity against numerous pathogens, as yet no NK receptors responsible for these activities have been identified. There is evidence, however, that other NK-cell receptors are involved in the protective response against poxvirus and influenza.8 Their study is warranted to provide new insight into the mechanisms of NK cell memory. In human NK cells, the killer cell immunoglobulin-like receptors (KIRs) are the functional equivalents of the mouse Ly49 receptors. Intriguing lines of evidence suggest that activating KIRs play an important role in the pathogenesis of human immunodeficiency virus and human CMV infection.9 Given these similarities with the NK cell response to virus in mice, it is not unreasonable to consider that antigen-specific stimulation of human NK cell receptors may lead to NK cell's immunological memory. Further, because of the important role of NK cells in graft rejection as well as in the control of certain tumors, the ability to harvest or deplete memory NK cells could have profound impact on the outcome of those diseases. Human NK cell memory might pave the way for new vaccine approaches, not only against chronic virus infections but also cancer, through controlled exposure to NK cell-dependent antigens. Thus far, specific antigen recognition directing a stronger response to ensuing challenges was only attributed to memory T and B cells. It now seems that the key attributes of adaptive immunity, from specific recognition to memory, have co-evolved in NK cells. It will be fascinating to learn more about the requirements for the triggering, regulation and maintenance of NK cell memory. Unraveling the networks that guide NK cells in host defense will continue to drive the clinical applications10 of, after all, a very sophisticated lymphocyte in the fight against infection and tumors. Natural killer (NK) cell response against mouse cytomegalovirus (MCMV) infection. (a) The Ly49H receptor recognizes the virally encoded protein, m157, on the surface of MCMV-infected cells. In wild-type NK cells, Ly49H is co-expressed with the adaptor protein DAP12, a signaling sub-unit that mediates Ly49H-dependent NK cell activation. DAP12−/− NK cells are deficient for NK cell receptor-activated signaling and for Ly49H expression. (b) Upon MCMV infection, the Ly49H+ subset of naïve NK cells (in pink) differentiate into effector cells and, later, into memory cells (red) with enhanced response abilities than naïve cells. (c) The kinetics of the NK cell response to MCMV infection is driven by the specific recognition of the viral protein, m157 by Ly49H receptor. NK cells expressing the Ly49H activating receptor (Ly49H+) will multiply clonally (Expansion) after MCMV infection contrary to the Ly49H− NK cells (1° MCMV infection). Once the infection is cleared, most of the propagated Ly49H+ NK cells will be eliminated (Contraction), leaving behind a small pool of long-lived memory cells (Maintenance) that ‘remembers’ how to fight with MCMV. The last phase occurs upon re-infection (2° MCMV infection) when memory NK cells will divide again to mount a stronger anti-viral response (Recall/Protection).

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