Genetic Labeling Reveals Altered Turnover and Stability of Innate Lymphocytes in Latent Mouse Cytomegalovirus Infection

Abstract

Mouse CMV (MCMV) infection rapidly induces the proliferation of NK cells, which correlates with immunological protection. Whether NK cells primed during acute response against MCMV are maintained for the long term is not known. In this study, we used TcrdH2BeGFP mice in which maturing NK cells are genetically labeled with a pulse of very stable histone-2B–eGFP. In this system, we found that the reporter protein was diluted out upon NK cell division during acute MCMV infection. At the same time, mature NK cells in uninfected mice showed only very limited turnover in vivo. Three months after primary infection when MCMV latency was established, the majority of peripheral NK cells still displayed a higher record of proliferation than NK cells in mock-infected controls. This observation included both Ly49H+ and Ly49H– NK cells. Conversely, naive NK cells did not show more proliferation after transfer into latently MCMV-infected mice than that after transfer into mock-infected control mice. This indicated that the observed alterations of the NK cell compartment in MCMV latency were “legacy” (i.e., resulting from prior events during the initial immune response). Together, these results suggest that antiviral immune responses induce sustained alterations of innate lymphocyte populations that extend far beyond the first days of acute infection.

The evolutionary arms race between NK cells and viruses: Who gets the short end of the stick?

“…By the same token, can we expect that the ligation of other MCMV‐specific Ly49 activating receptors will lead to a similar sort of virus‐specific NK‐cell memory? Although there is still no other evidence for MCMV‐specific NK‐cell memory, except the one via Ly49H receptor engagement, it is important to emphasize that even months after primary infection the majority of peripheral NK cells, including both Ly49H + and Ly49H − NK cells, display a higher proliferative capacity compared with that of NK cells in control (uninfected) mice; thus, primary antiviral immune responses induce long‐term alterations in NK cells . This is in line with a more recent study showing a higher expression of CD25, the high‐affinity IL‐2 receptor, on NK cells upon MCMV infection .…”

Cardiac c-Kit Biology Revealed by Inducible Transgenesis

“…Doxycycline-mediated transgene induction can be performed at any stage of development without the potential adverse side effects of tamoxifen treatment in pregnant dams 52–57 . Protein stability of H2BEGFP, with a reported half-life of several months in vivo 44, 58 , provides long term tagging of c-Kit+ cells in CKH2B mice, while allowing for reversibility in mitotically active systems. Permanent tagging of c-Kit cells allowing for long-term lineage tracking of cells has been initiated through combining the c-KitrtTA transgenic construct with a tetracycline-responsive Cre line 59 and the ROSA mT/mG reporter mouse 60 .…”

Homéostasie des cellulesnatural killer

“…Ce point a été abordé en mesurant l'incorporation de BrdU Cette étude conclut que la « mémoire » NK est de courte durée au contraire de la mémoire T qui est stable pendant au moins un an après l'infection. À l'inverse, une autre étude dans le modèle MCMV conclut que l'homéostasie des cellules NK et, en particulier, leur prolifération sont encore modifiées plusieurs mois après l'infection [37]. Si la pertinence physiologique de la mémoire NK et la persistance de ( bromodéoxyuridine) par les cellules NK de souris à l'état basal [24] : 50 % des cellules NK périphériques étaient marquées en 17 jours, suggérant une demi-vie de 17 jours en périphérie.…”