378
Antigen Presenting Cells (APCs)
Unmethylated
CpG
nucleotides,
orga-
nized in palindromic stretches are rather
rare in mammalian DNA. If enough of
these CpG sequences accumulate intracel-
lularly, macrophages start secreting IFN-
γ
and IL-12. According to recent results, this
response is mediated via TLR-9.
Two other receptors of the TLR family,
which are functionally investigated are
TLR-5 and TLR-3. TLR-5 was found to
bind the bacterial motor protein flagellin,
whereas TLR-3 is discussed to bind viral
dsRNA. The functions of other proteins
of the TLR family, which comprises 10
members, are currently being explored.
8.3
Macrophage Activation
Unactivated macrophages stand out for
their high rate of phagocytosis and chemo-
tactic movements and they proliferate.
This is suf±cient to cope with low numbers
of pathogens in an antigen-independent
way. However, in order to function as an
APC and to gain high antimicrobial effec-
tiveness, macrophages have to be activated.
Such an activated macrophage can damage
a broad spectrum of microbes and even
certain tumor cells, but also healthy self-
tissue. Therefore, macrophage activation
must be tightly regulated. This regulation
is achieved through the requirement of two
coinciding signals. Signal 1 is provided by
IFN-
γ
, signal 2 can be provided by differ-
ent means, for example, LPS, engagement
of CD40L, or cognate TCR (Fig. 7).
Activated CD4
+
T
H1
cells can deliver
both signals very ef±ciently: they secrete
high doses of IFN-
γ
and express CD40L.
Activated CD8
+
CTLs also secrete IFN-
γ
; however, recognition of MHC-antigenic
peptide complexes by macrophages is not
always suf±cient to attain full activation
of macrophages – the presence of low
amounts of LPS or membrane TNF-
α
can compensate for the lack of CD40L
on CD8
+
T cells.
IFN-
g
Activated
T
H1
cells
NK cells
Activated
T
H1
cells
CTLs
LPS or
CD40L
Resting
macrophage
Activated
macrophage
Primed
macrophage
MHC I
LFA-1
TNF
receptor
CD40
IL-12
IL-1
CD80
TNF-
a
O
2
NO
MHC II
LFA-1
MHC I
MHC II
MHC I
Fig. 7
The two-step model of macrophage
activation. In the Frst step, resting macrophages
are primed by I±N-
γ
secreted by activated T
H1
or
NK cells. ±ully activated macrophages are
generated in a second step upon encounter of
CD40L or LPS. Activated macrophages express
MHC class II molecules, costimulators, for
example, CD80, CD40, and the TN± receptor.
They secrete the cytokines IL-12, IL-1, and TN±-
α
and the radicals NO and superoxide (O
2
).
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