Literature Watch Implications for transplantation

Field: Medicine (Health Sciences)

A pair of new studies reveal that epigenetic changes alter NK cell reactivity following CMV infection. A pair of new studies reveal that epigenetic changes alter NK cell reactivity following CMV infection. CITATION: Lee J, Zhang T, Hwang I, Kim A, Nitschke L, Kim M, et al. Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals. Immunity 2015; 42: 431–442. CITATION: Schlums H, Cichocki F, Tesi B, Theorell J, Beziat V, Holmes TD, et al. Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 2015; 42: 443–456. Cytomegalovirus (CMV) has been intimately associated with the human race across evolutionary time and is an important contributor to infectious morbidity following transplantation. Myriad studies in both transplantation and autoimmunity conducted over the last decades have revealed a potent influence of CMV in shaping the human T cell repertoire and T cell differentiation programs, including emergence of immunosuppression-resistant CD28- cells. In contrast, the effect of CMV infection on natural killer (NK) cell immunity, and any resultant impact on alloimmunity, is less well understood. Seminal studies from the late 2000s began to interrogate the effect of CMV infection on the NK cell compartment, and in so doing uncovered memory-like qualities of NK cells—changes that occurred in NK cell populations following CMV infection that were analogous to changes that occurred during the differentiation of memory CD8+ T cells. Work over the last decade has revealed that memory-like NK cells associated with CMV positivity can be identified by their upregulation of the activating receptor NKG2C, but has also shown that paradoxically, NKG2C+ memory-like NK cells respond poorly to human (H)CMV-infected T cells. This apparent inconsistency was clarified in the studies referenced above when it was discovered that NKG2C+ memory-like NK cells actually exhibit superior functional responsiveness to CMV-infected target cells relative to conventional NK cells when CMV-specific antibody is present. These data suggest the provocative idea that memory-like NK cells possess increased potency not through direct recognition of infected cells, but indirectly through antibody-dependent recognition via CD16. Why do memory-like NK cells elicited following CMV infection exhibit altered signaling and effector function relative to conventional NK cells? The studies by Schlums et al and Lee et al reveal that altered DNA methylation patterns in NK cells following CMV infection result in a loss of expression of B cell– and myeloid cell–related signaling proteins including Syk, FceRg, EAT-2 and PLZF, and a shift toward gene expression patterns observed in CD8+ T cells. Thus, epigenetic changes underlie adaptive NK cell differentiation observed following CMV infection. Together, these studies uncover the mechanism by which NK cell populations diversify in response to viral infection, and put forth the paradigm that while NK cells are not adaptive in the classical sense of altered antigen specificity, adaptation within the NK cell compartment derives from epigenetic modification, which drives the emergence and persistence of specialized NK cell subsets that each have distinct functional characteristics. These results have implications for transplantation in that they offer new insight into additional ways in which CMV fundamentally shapes immunity. Interestingly, it has been previously noted that NKG2C+ NK cells do expand and accumulate in transplant recipients experiencing CMV reactivation and, consistent with their memory-like properties, such cells persist long term in these patients even after resolution of active infection. Thus, future investigation should be aimed at interrogating the relative alloreactive potentials of conventional versus memory-like NKG2C+ T cells that emerge in the face of CMV infection. Furthermore, the observation that memory-like NK cells exhibit enhanced effector function in an antibody-dependent manner puts forth the intriguing possibility that memory-like NK cells, driven by the presence of CMV, may collude with alloantibody in mediating damage to the graft. It is also tempting to note that memory-like NK cells exhibited DNA methylation patterns similar to those observed in CD57+ effector CD8+ T cells. If virally elicited memory-like NK cells retain the ability to recognize and respond to allogeneic tissue, one might speculate that these cells may also exhibit properties of resistance to immunosuppression similar to those observed in CD57+ effector CD8+ T cells. Future studies on the relative alloreactive potential, as well as susceptibility to immunoregulation, of diverse NK cell subsets driven by CMV will broaden our understanding of the role of NK cells in alloimmunity.