Scientists from the German Cancer Research Center (DKFZ) have found out that natural killer cells
need at least two separate signals in order to be able to fight
cytomegaloviruses. This finding might help to find more effective
treatments against this virus, which is particularly dangerous for
leukemia patients in the wake of bone marrow transplants.
In healthy people, infections with human cytomegalovirus
(HCMV) normally do not cause any symptoms. By contrast, in persons with a
weakened immune system such as leukemia patients in the wake of a bone
marrow transplantation, the virus can lead to life-threatening
complications. HCMV is also life-threatening for unborn babies. No other
pathogenic agent is transferred so frequently during pregnancy from the
mother to the fetus.
A well functioning immune defense of the
body normally keeps the viruses in check, primarily using its “innate
arm”* with its prime “weapons” called natural killer cells (NK cells). A
small portion of these killer cells has an activating receptor molecule
called CD94/NKG2C on their surface. It is exactly this group of NK
cells that multiplies strongly during an HCMV infection. So far, the
molecular signals underlying this process had remained in the dark; now
they have been deciphered.
In order to determine the factors that are required for the specific
NK cell proliferation during an HCMV infection, researchers in the
department of Dr. Adelheid Cerwenka at the German Cancer Research Center
(Deutsches Krebsforschungszentrum, DKFZ) cultivated HCMV infected
connective tissue cells along with immune cells from the blood of
healthy donors.
They found out that specific immune cells – monocytes that carry the
surface marker CD14 – are indispensable for the proliferation of NK
cells carrying CD94/NKG2C because they produce a chemical messenger
called IL-12. When the researchers neutralized IL-12, the NK cell
proliferation was strongly reduced. However, not only the chemical
messenger is necessary but also the actual presence of the CD14
monocytes.
Cerwenka’s team additionally discovered that NK cells carrying
CD94/NKG2C proliferate only if the infected cells exhibit the HLA-E
molecule on their surface. HLA-E is the binding partner of the receptor
CD94/NKG2C. It is closely related to the presentation molecules that are
indispensable for antigens in adaptive immunity. HCMV infected cells
increase the production of HLA-E.
“The activation of the NK cells by the cytomegalovirus is a complex
process that involves many different molecules. We have now been able to
identify a signal 1 (mediated by HLA-E) and a signal 2 (mediated by
IL-12 and monocytes) that are both necessary for the proliferation of NK
cells that exhibit the activating CD94/NKG2C receptor,” says Alexander
Rölle, one of the two first authors of the publication.
“This activation strongly resembles the double signal that is
required to make the adaptive immune system ready to attack,” says
Adelheid Cerwenka, an immunologist at the DKFZ, who headed the study.
She continues: ”Following an activating contact with an antigen (signal
1), the T and B cells of the adaptive immune system need the presence of
so-called co-stimulating signals (signal 2) in order to multiply and
thus mount a defense. The exact knowledge of these interactions may help
us to treat patients with life-threatening HCMV infections more
effectively by supporting the activation of their NK cells. Since NK
cells also play an important role in tumor defense, this finding might
also advance the development of cancer immunotherapies.”
Alexander Rölle, Julia Pollmann, Eva-Maria Ewen, Anne Halenius,
Hartmut Hengel and Adelheid Cerwenka: IL-12-producing monocytes and
HLA-E control HCMV-driven NKG2C+ NK cell expansion. Journal of Cinical
Investigation 2014, DOI: 10.1172/JCI77440
*The body’s defense system is made up of the innate and the adaptive
immune systems. The innate system is responsible for immediate defense
of the body. Cells of the innate system do not have specific receptors
but respond to a broad spectrum of pathogens (using phagocytes,
granulocytes) or transformed body cells (using NK cells). By contrast, T
and B lymphocytes, which are part of the adaptive immune system, are
equipped with highly specific receptor molecules directed against
protein components of specific pathogens. If these long-lived cells,
which form a sort of memory of the immune system, encounter this
specific invader again, they first have to multiply before they can
mount an effective defense. Therefore, several days pass before the
adaptive immune defense is ready to fight the attack