Download IN THIS ISSUE Precursor loss triggers AIDS A MyD88 meddles with

Published August 20, 2007
IN THIS ISSUE
Precursor loss triggers AIDS
A MyD88 meddles with survival
In the MyD88 family of cytosolic
adaptor proteins, the newest member
is the group’s black sheep, according
to Kim et al. (page 2063). Whereas
most MyD88 proteins turn on antipathogen responses within myeloid
cells, the rebel, MyD88-5, instigates
cell death within neurons.
MyD88-1–4 all respond to Toll-like
receptor (TLR) activation in leukocytes and stimulate innate immune
responses. MyD88-5, however, does not
transmit TLR signals or induce innate
response genes. Two extra domains in
MyD88-5 that may allow it to interact
with cytoskeletal proteins hint at an
entirely different function.
Kim et al. now find that the protein
is not even expressed in most leukocytes and instead is found mainly in
neurons. There, MyD88-5 bound to
microtubules and studded the outer
2010
membranes of mitochondria. Mitochondria formed clusters when MyD88-5
expression levels were high but were
unable to group when the two protein
interaction domains of MyD88-5 were
removed. By linking them to the
microtubules, MyD88-5 probably enables the mitochondria to get around
efficiently within the neuron, where
these energy stores must travel long
distances. But how MyD88-5 levels are
controlled within the neuron remains
to be determined.
MyD88-5 also recruited JNK3, a
kinase whose association with mitochondria activates apoptosis in stressed
cells. The stress of UV light increased
the association of JNK3 with MyD88-5,
and neurons from mice lacking MyD88-5
were less vulnerable to stress-induced
apoptosis. The authors are now using
mouse models of brain injury to investi-
Proapoptotic JNK3 (yellow) clusters near
mitochondria (red) only when MyD88-5
(green) is present.
gate whether the absence of MyD88-5
saves damaged neurons during, for example, a stroke.
T cells also expressed some MyD88-5.
Because these cells lack JNK3, the
adaptor probably has additional binding partners.
JEM Vol. 204, No. 9, 2007
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HIV and its simian counterpart, SIV, replicate rapidly after infection but often
take many years to subdue the immune system and cause AIDS. Okoye et al.
(page 2171) now find that these slow burner viruses only cause disease after
they deplete the precursor cells that give rise to pathogen-fighting effector cells.
The effector memory T (TEM) cells that battle these viruses at infection
sites develop from a pool of CD4+ central memory (TCM) cells that are stored
in secondary lymphoid organs. Although the virus infects both types of cells
simultaneously, TEM cells are the first casualties. This early depletion of TEM
cells is not completely devastating; the TCM population quickly cranks out
more TEM cells. But this defensive strategy is obviously not foolproof:
infected individuals eventually develop AIDS.
Okoye et al. now identify the glitch in the strategy by tracking disease
progression in SIV-infected rhesus macaques. Newly generated TEM cells were
short lived, they found, as persistent activation by the virus induced their death.
And unlike in earlier stages of infection, TCM cells no longer came to the rescue,
Loss of TCM cells during chronic SIV infection (bottom)
as they were also crippled by viral infection. The virus thus tamed the immune
depletes pathogen-fighting TEM cells and triggers AIDS.
system by stimulating one population to death and destroying its back-up.
Based on these results, stabilizing the TCM pool may be a more effective way to prevent the onset of AIDS than
controlling viral load—the goal of current vaccination strategies. Rising viral loads might not be the trigger for AIDS,
as viral loads remained constant while CD4+ T cell levels declined during the later stages of disease.
Recent studies from other groups show that survival of patients with AIDS correlates with more
circulating TCM cells, supporting the idea that protecting the TCM niche might keep AIDS at bay. The team
is now trying to identify the factors that bolster TCM cell levels and how HIV/SIV dismantles them.
Published August 20, 2007
Text by Hema Bashyam
[email protected]
T-bet terminates self-renewal
The transcription
factor T-bet is
expressed mainly
in TEM cells.
A T cell transcription factor favors short-term
benefits over long-term stability, according to a new
study by Intlekofer et al. (page 2015).
Long-term protection against pathogens by
CD8+ T cells is due to a self-renewing population of
central memory (TCM) cells that circulate in the
lymph nodes. When they see their target antigen,
these cells first rapidly proliferate, become cytotoxic,
and then head out to the periphery to fight the
invaders. A faster attack mode is provided by effector
memory T (TEM) cells, which are already in the
periphery, but these cells quickly die out.
Memory T cell development requires a
transcription factor called T-bet. Intlekofer et al.
now find that mice lacking T-bet have plenty of
TCM cells but lack the TEM pool. In normal mice,
only the TEM cells expressed T-bet, suggesting that
T-bet skews the balance between the two
populations by driving the differentiation of
activated CD8+ T cells into TEM cells.
CD8+ memory T cell development also requires
signals from CD4+ T cells. The team found that
these signals favored the growth of CD8+ TCM cells.
Mice that lacked CD4+ T cells therefore had higher
numbers of TEM cells than TCM cells. This expanded
TEM population had high levels of T-bet protein.
Deletion of T-bet corrected this defect by restoring
the numbers of self-renewing cells.
T cell education
dictates function
On page 2053, Ghosh et al. reveal how antiinflammatory COX-2
inhibitors cause dangerous cardiac side effects. COX-2, they find,
is needed to shut off an important clotting protein.
COX-2 is produced during infection and injury by the endothelial
cells that line blood vessels. The enzyme converts a cellular lipid
known as arachidonic acid into lipids that instigate fever, pain, and
other uncomfortable hallmarks of inflammation.
COX-2 inhibitors such as Vioxx were popular antiinflammatory
drugs until some users began to suffer serious side effects such as
heart attack and stroke.
Ghosh et al. now find that the normally cardioprotective effect of
COX-2 stems from its metabolic conversion not of arachidonic acid,
but of other substrates: the endocannabinoids. Byproducts of these
lipids, they found, activated a nuclear receptor and transcription
factor, PPARδ, that suppressed the gene for tissue factor (TF)—
a protein that activates blood clotting. Mice that were given COX-2
inhibitors had high levels of TF that could then be decreased by
activating PPARδ. The side effects triggered by the COX-2 inhibitors
in humans may thus be due to the overproduction of TF.
COX-2’s anticlotting role probably keeps injured vessels free
of clots while the damage is being repaired. The team is now
investigating whether patients who have adverse reactions to the
drugs have defects in TF or other clotting genes.
How a young T cell is educated may dictate its
future function, according to a new report by Li
et al. (page 2145).
Young T cells receive survival signals through
their T cell receptors during development. These
signals are normally provided by epithelial cells in the
thymus. But recent reports show that CD4+
thymocytes also signal to each other.
When stimulated by antigen, epithelium-educated
CD4+ thymocytes can become helper T cells of all
varieties—T helper (Th)-1, Th2, or Th17 cells—
depending largely on the surrounding cytokines. But
self-educated thymocytes, Li et al. now find, fail to
make this lineage choice. These cells rapidly generated
both interferon (IFN)-γ and interleukin (IL)-4, even
when stimulated under conditions that normally inhibit
IL-4 production. A ready-to-fire IL-4 locus and
preformed IL-4 mRNA in the developing cells
explained their tendency to continue synthesizing IL-4.
Mice whose thymocytes were forced to signal to
each other to survive were less likely to develop allergic
inflammation than were mice whose T cells developed
normally. This protective effect might be due, the
authors speculate, to the suppression of pro-allergic IL-4
by the IFNγ produced by these cells. Thus, people who
have more self-educated T cells may be less allergy
prone. But assessing the relative numbers of the two cell
types in humans is difficult, as distinguishing surface
markers have yet to be identified.
The team is now investigating how T cells decide
between a thymocyte- and an epithelial cell–based
education and how thymocyte-to-thymocyte signals
set the cells up for an IL-4–producing future.
A COX-2 inhibitor (right) increases the expression of tissue factor (red)
in heart vessels (arrows).
IN THIS ISSUE | The Journal of Experimental Medicine
2011
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Following the trail
from COX-2 to clotting