Expansion and Contraction of the NK Cell Compartment in Response to Murine Cytomegalovirus Infection

Abstract

NK cells are capable of responding quickly to infectious challenge and contribute to the early defense against a wide variety of pathogens. Although the innate NK cell response to murine CMV (MCMV) has been extensively characterized, its resolution and the fate of the activated NK cell population remains unexplored. Herein, we characterize both the expansion and contraction phases of the NK cell response to MCMV. We demonstrate that NK cell recruitment into the immune response to MCMV infection is restricted to the first 3 days of infection and as the peripheral NK cell compartment expands, NK cells undergo accelerated phenotypic maturation. During the resolution of the immune response, NK cell compartmental contraction is marked by the selective death of responding NK cells. Additionally, throughout the infection, a naive NK cell pool that remains responsive to additional stimuli is actively maintained. These findings illustrate the plasticity of the NK cell compartment in response to pathogens and underscore the homeostatic maintenance of the resting peripheral NK cell pool.

NK Cell Maturation and Peripheral Homeostasis Is Associated with KLRG1 Up-Regulation

“…KLRG1 expression was confined to the mature Mac-1 ϩ subset of NK cells, whereas the KLRG1 Ϫ population was comprised of both Mac-1 ϩ and Mac-1 Ϫ NK cells (Fig. 3a), these data being consistent with an earlier report of KLRG1 expression following MCMV infection (25). The distribution of KLRG1 expression on NK cells was confirmed by tracking CD27 and Mac-1 expression, because KLRG1 and CD27 appear mutually exclusively expressed on NK cells (Fig.…”

“…This finding was extended by our recent report on NK subsets where Mac-1 ϩ CD27 Ϫ KLRG1 ϩ cells were found to produce poor levels of IFN-␥ following stimulation with IL-12 and IL-18, cytokines required for the NK cell expansion during MCMV infection (28) or when cocultured with dendritic cells (23). In addition, KLRG1 ϩ NK cells appear to preferentially down-regulate bcl-2 during the course of MCMV infection (25). These findings, together with our report that KLRG1 ϩ NK cells have impaired turnover and responsiveness to IL-15, suggest a model where expression of KLRG1 may dampen or terminate NK cell responses, although the mechanism for this function is yet to be elucidated.…”

“…These studies identified the fact that NK cells responding to MCMV acquired KLRG1, and these cells contained less intracellular IFN-␥ compared with the KLRG1 Ϫ population (12,25). This finding was extended by our recent report on NK subsets where Mac-1 ϩ CD27 Ϫ KLRG1 ϩ cells were found to produce poor levels of IFN-␥ following stimulation with IL-12 and IL-18, cytokines required for the NK cell expansion during MCMV infection (28) or when cocultured with dendritic cells (23).…”

DAP12 Signaling Directly Augments Proproliferative Cytokine Stimulation of NK Cells during Viral Infections

“…Selective NK cell proliferation has also been observed during infection with the poxvirus vaccinia, demonstrating that this is not an MCMV-or even herpesvirus-restricted phenomenon (15). After resolution of the infection, the NK cell population contracts back to steady-state levels (20,24).…”

Homéostasie des cellulesnatural killer

“…Cette prolifération est beaucoup plus forte dans la moelle osseuse que dans les autres organes, ce qui confirme le rôle majeur de ce tissu dans la production des cellules NK [16]. La production de nouvelles cellules NK est contrebalancée par la mort de cellules NK matures CD11b + CD27 -KLRG1 + dans différents organes [25]. La prolifération homéostatique des cellules NK peut augmenter lorsque ces cellules sont transférées dans des souris lymphopéniques, selon un phénomène entièrement dépendant de l'IL-15 qui est disponible en plus grande quantité dans ces souris [26].…”