Antigen Presenting Cells (APCs)
379
Another source of IFN-
γ
,w
h
i
c
hi
s
rapidly available at the onset of an in-
fection,
is
NK
cells,
thus
supporting
T
H1
-mediated macrophage activation. T
H2
cells counteract macrophage activation in
that they secrete IL-10 but not IFN-
γ
.
Macrophage activation by T
H1
cells ex-
pressing CD40L and secreting IFN-
γ
is
central to the host response to pathogens
that proliferate in macrophage phago-
somes, such as
Mycobacteria tuberculosis
,
Mycobacteria leprae
or
Leishmania
species.
The same is true for vaccinia virus. Ac-
tivated macrophages can clear internal
microbes by overcoming the block in fus-
ing phagosomes with lysosomes, so that
lysis and degradation in phagolysosomes
can occur. More importantly, activated
macrophages produce the bactericidal ni-
trogen metabolite NO (see below).
By the late 1960s, the basis of ac-
quired cellular immunity to facultative
and obligate intracellular parasites was as-
cribed to activated macrophages. E. Metch-
nikoff wrote ‘‘The acquisition of immunity
against microorganisms is therefore due
not only to the change from negative to
positive chemotaxis but also to the perfec-
tion of the phagocytic and digestive powers
of the leukocytes – a general superactivity
and adaptation of the phagocytic reaction
is produced.’’
8.4
Immunological and Nonimmunological
Effector Functions
8.4.1
Microbial Killing
T
H1
cells activate infected macrophages
through
their
TCR
engaging
MHC
class
II–antigenic
complexes
on
the
macrophage
surface
and
the
focal
secretion
of
IFN-
γ
.
The
consequence
is a series of events that converts the
macrophage into a potent antimicrobial
effector cell. An important intracellular
event,
which
can
be
nicely
observed
by modern microscopy technologies, is
the induced fusion of phagosomes with
lysosomes, thereby exposing intracellular
or
recently
ingested
microbes
to
microbicidal lysosomal hydrolases leading
to their destruction.
Other
changes
render
macrophages
more potent APCs and thereby help am-
plify an adaptive immune response: sur-
face MHC class II, CD80, CD86, LFA-1,
CD40, and TNF receptor are upregu-
lated, thereby increasing the ef±cacy of
macrophages in presenting antigen to rest-
ing CD4
+
T cells and the responsiveness
to CD40L and TNF-
α
.
TNF-
α
synergizes with IFN-
γ
in induc-
ing the enzyme inducible NO synthetase
(iNOS), which produces the reactive ni-
trogen metabolite NO. NO together with
oxygen radicals are secreted by activated
macrophages leading to cell damage in
the close neighborhood. Together with
secreted proteases, NO and O
2
radicals
a
r
ee
v
enab
l
et
oa
t
t
a
c
kl
a
r
g
ee
x
t
r
a
c
e
l
lu
-
lar pathogens such as parasitic worms,
which cannot be ingested, or intracellular
pathogens that resist or survive phagolyso-
some fusion. The price to pay is that host
tissue is destroyed as well by radicals and
other toxic mediators.
Fully activated macrophages also secrete
various types of cytokines, for example,
TNF-
α
, IL-1, IL-6, and IL-12. IL-1 increases
the
access
of
effector
T
cell,
TNF-
α
is an autocrine stimulus and increases
the
vascular
permeability,
IL-6
favors
lymphocyte activation and IL-12 favors
differentiation of CD4
+
T cells into T
H1
cells and activates NK cells.
Besides priming macrophages through
the focal secretion of IFN-
γ
,T
H1
cells
are very important in the recruitment of
macrophages to sites of infection. This
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