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Novel NK cell subsets – Lessons from HCMV and MCMV

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Natural Killer (NK) cells have been studied for roughly 40 years. Their pivotal role in the early defense against malignant transformation and viral infection is well established. Traditionally, they are considered innate effectors, eventually shaping subsequent adaptive responses, but nonetheless, are ...

Natural Killer (NK) cells have been studied for roughly 40 years. Their pivotal role in the early defense against malignant transformation and viral infection is well established. Traditionally, they are considered innate effectors, eventually shaping subsequent adaptive responses, but nonetheless, are short-lived and limited in their specificity. During the last decade, however, novel, previously unappreciated aspects of NK cell biology have received increased attention. Hallmarks such as subset expansion and long-lasting functional alterations share traits with certain features of adaptive immune responses. Consequently, certain NK cell populations are now referred to as “adaptive” or “memory-like” subsets.

Two pathogens have arguably been the key for unveiling the adaptive nature of certain NK cell subsets in both mice and humans: Human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV). Susceptibility to CMV infection is characteristic for NK cell-deficient patients and mice alike, and cytomegaloviruses devote a wide range of viral immune evasins to escape NK cell-mediated immune responses, suggesting an intense co-evolution of virus and host.

Studies on HCMV ultimately led to the identification of NK cell subsets with distinct phenotypic, functional, transcriptional and epigenetic profiles, that differ substantially from conventional/canonical NK cells. Intriguingly, exposure to HCMV seems to be a necessary pre-requirement for the formation of adaptive NK cells, even though the initial events leading to subset formation remain enigmatic. The surprising heterogeneity of this HCMV-induced adaptive NK cell compartment raises exciting new questions regarding their origin, regulation, specificity, function and therapeutic potential. In MCMV infection, the mechanisms leading to the generation of highly antigen-specific NK cell memory have been partially deciphered allowing deeper insights into the molecular mechanisms of memory formation within the innate immune system.

In this Research Topic, we welcome the submission of Review, Mini-Review, Original Research, Brief Research Reports, Perspective and Opinion articles that cover, but are not limited to, the following topics:

1. Function and regulation of adaptive NK cells.
2. Heterogeneity of adaptive NK cell subsets.
3. HCMV reactivation and adaptive NK cells in transplantation.
4. Epigenetics of adaptive NK cells.
5. Responses of HCMV-induced NK cells in heterologous infections.
6. Mechanisms of NK cell memory formation in MCMV infection.
7. Evasion mechanisms of HCMV and MCMV targeting NK cell responses.
8. Memory-like NK cells in mice and humans.


Keywords: NK cell, Natural killer cell, HCMV, MCMV


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