Discoveries by Drexel Scientists Shed Light on
the Dual Nature of Immune Defense Mechanisms
When you acquire a short-lived, acute infection such as
seasonal influenza, the body responds in a coordinated
fashion to rapidly clear the invading pathogen. Then, upon
completion of its mission, the army of effector immune cells
stands down, leaving a troop of memory sentinels behind
in case the invader returns. This immune response requires
cross-talk and collaboration between innate (first lines of
defense) and comprehensive adaptive (reserve) battalions
to mount a strong and effective attack. However, regulating
the intensity of the siege is also important to minimize
casualties of war.
Researchers in the laboratory of Peter D. Katsikis, MD,
PhD, have shown just how this occurs. Their findings,
reported in Nature Immunology1, provide new insight into
how the intricate responses of certain types of white blood
cells (killer CD8+ T cells) are controlled.
A linchpin that harnesses the appropriate immune
responses and aids in the establishment of long-term
immunological memory is microRNA-155. These small
molecules originate from DNA, but are not translated into
proteins; instead, microRNAs regulate gene expression by
imperfectly pairing with related messenger RNA sequences.
This degrades the RNA or blocks protein synthesis from it.
When killer T cells are activated in response to viral or
bacterial infections, microRNA-155 expression increases,
and this affects the sensitivity of those cells to type I
interferon (IFN) — proteins that make up the biochemical
bulwark of the innate defense system. Following non-specific
detection of an invader, these type I IFN messengers
“alert” surrounding cells by initiating protective defenses.
This research sheds light on an unresolved enigma involving
the regulation of type I IFN signaling in killer T cells. Paradoxically,
these chemical messengers mediate both increased
expansion (build up the troop strength) and diminished growth
of these cells (downsize the force). The study, authored by
Donald Gracias, PhD; Erietta Stelekati, PhD; and colleagues,
identifies a previously unknown role for microRNA-155,
in tipping the balance in favor of immune expansion and,
in turn, improved control of viral infections.
Katsikis, professor of microbiology and immunology, and
senior author of the paper, explains, “The IFN paradox
— that is, why IFN sometimes inhibits but other times
enhances T cell immunity — has been a long-lasting puzzle
for immunologists. Our studies have uncovered some of the
molecular mechanisms at work.”
But what about long-term, chronic infections such as
those caused by HIV and hepatitis C virus? In these types
of infections, the immune system and the pathogen fight to
the point of a prolonged stalemate, during which neither
the invader nor the defender prevails. However, as time
progresses, persistent and excessive immune responses
kill battle-fatigued T cells, as well as innocent bystanders,
giving the enemy pathogen an advantage.
In a related paper published in PLoS Pathogens2, the
Katsikis laboratory uncovered the mechanism by which the
same type I IFN mediators render T cells sensitive to death.
In chronic HIV infection, there is an ongoing production of
these chemical messengers that is likely triggered by the
presence of the enemy virus. The research shows that
helper CD4+ T cell death (a hallmark of HIV disease) is
mediated by type I IFN and its ability to increase Bak, a
gene that is a major factor in cellular death. Not only did
type I IFN exposure make healthy helper T cells sensitive to
death in the same way and to a similar extent as HIV-positive
patient T cells, but elevated type I IFN–stimulated gene
expression in HIV-infected patients was also associated with
accelerated helper T cell death and loss.
This study, authored by Joseph Fraietta, PhD, and
colleagues, highlights that the decline of T cells in the blood
in HIV disease is not largely due to direct viral infection, but
is instead a bystander effect of excessive immune responses
involving type I IFN (too much collateral damage). Importantly,
the research also shows for the first time that,
although type I IFN production may be protective during
acute (early stage) AIDS virus infections, the beneficial
effects of these cytokines are lost during the chronic (late)
stage when they harm the immune system by killing helper
T cells. Indeed, experiments in the study involving monkeys
infected with simian immunodeficiency virus, which is
closely related to HIV, show that the interferon response
may exert an opposing effect on viral control that is
dependent on the stage of infection (early versus late).
Thus, while battling acute viral infection may require a
“strike hard and often” approach, careful tempering and
appropriate deployment of specific immune responses are
needed to win the war against chronic disease.
This article originally appeared in the January/February 2014 issue of Pulse, the newsletter of Drexel University College of Medicine.
1 Nature Immunology, 14: 593–602, 2013.
2 PLoS Pathogens, 9(10):e1003658, 2013.