Science - USA (2021-07-16)

(Antfer) #1

276 16 JULY 2021 • VOL 373 ISSUE 6552 SCIENCE



By Carl Nathan


he cytokine interferon-g (IFN-g),
when released by lymphocytes, aug-
ments the capacity of macrophages
and other host cells to kill certain
intracellular protozoa, bacteria, and
viruses (1–3). However, the function
of most of the hundreds of genes induced
by IFN-g is unknown, and biochemical
mechanisms of pathogen inactivation are
incompletely understood. On page 296 of
this issue, Gaudet et al. ( 4 ) identify an ef-
fector mechanism in the human immune
system: production of IFNg–induced apo-
lipoprotein L3 (APOL3) in epithelial cells,
endothelial cells, and fibroblasts that acts
like a detergent, extracting lipids from
membranes of bacteria in the cytosol, kill-
ing the bacteria. Not only does APOL3
dissolve a biophysical boundary—the bac-
terial inner membrane—but the findings
of Gaudet et al. help dissolve conceptual
boundaries about the composition of the
immune system.
In 1882, Metchnikoff launched the field
of immunology with a microscope, a thorn,
and a starfish. Seeing cells gather where the
thorn punctured the larva, he declared that
phagocytic cells defend the host from invad-
ing microbes. Ehrlich favored soluble factors.
By the 1950s, the paradigm was set: Both
cells and soluble factors are required; the im-
mune cells are macrophages, granulocytes,
and lymphocytes; the soluble factors are
chiefly antibodies and proteins collectively
called complement because they are needed
to lyse cells that antibodies tag for destruc-
tion. From the mid-1970s, immunologists dis-
tinguished dendritic cells from macrophages
and denominated lymphocyte subsets, but
the list of cell types in the immune system re-
mained restricted. That the liver is the major
source of complement and other host defense
proteins did not earn hepatocytes member-
ship in the immune system.
The boundary between what is and is
not part of the immune system has recently
sprung more holes with the recognition
that besides the liver, the nervous system
( 5 , 6 ), epithelia (6–8), erythrocytes ( 6 ), and

microbiota (7–9) are key contributors to
mammalian immunity. Gaudet et al. further
integrate diverse cell types into the immune
system by showing that they can deploy an
IFN-g–induced restriction factor against
bacteria in their cytosol (see the figure).
The findings of Gaudet et al. also weaken
a conceptual boundary established in the
early 1990s, when immunologists divided
the immune system into two modes, innate
and adaptive. Innate immunity, it was pro-
posed, kills pathogens directly. Individual
granulocytes and macrophages of the innate
immune system are not clonally distinct, so

large numbers can be mobilized quickly, but
they lack specificity and memory. Adaptive
immunity depends on lymphocyte clones
that proliferate upon encountering a specific
antigen for which they display a receptor.
Persistence of expanded clones with high-
affinity receptors provides memory. This
binary view accommodated some cross-talk:
Dendritic cells present antigen to lympho-
cytes along with signals that prepare them
to proliferate; lymphocytes recognizing an-
tigen secrete IFN-g to instruct macrophages
to increase their killing capacity and make
antibodies that frustrate pathogens’ attacks
or mark them for destruction by phagocytes
or complement. However, recent discoveries
highlight the importance of innate lympho-
cytes that lack antigen receptors. Such cells
can make IFN-g, including at the command
of granulocytes ( 10 ), bypassing adaptive
cells. Lymphocytes that have antigen recep-
tors can kill bacteria ( 11 ) without relying on
innate cells. Persistent epigenetic changes
can endow innate lymphocytes and macro-
phages with memory ( 12 ).
The study of Gaudet et al. adds support
to the following points of view. Every type
of non–disease-causing cell resident in
a human can potentially be a part of the
immune system. Lymphocytes and macro-
phages can work in both innate and adap-
tive modes. Biochemically, cells kill other
cells or themselves in a limited number of
convergently evolved but divergently acti-
vated ways, including by making holes in
membranes (shooting); oxidizing cellular
constituents (burning); and (in)activating
multiple enzymes and channels (poison-
ing). The immune system’s challenge is to
optimally deploy its effectors against faster-
evolving foes, minimize collateral damage,
and help to repair it.
APOL3 alone did not disrupt the inner
membrane of Gram-negative bacteria. Other
IFN-g–induced factors made the bacteria
susceptible to APOL3, including guanylate-
binding protein 1 (GBP1) ( 4 ). This guanosine
triphosphate (GTP)–hydrolyzing enzyme dis-
rupted the outer bacterial membrane, allow-
ing APOL3 access to the inner membrane.
It will be interesting to examine whether
apolipoproteins and GBPs cooperate to kill
mycobacteria, whose maintenance of an
outer lipid layer is analogous to that of Gram-
negative bacteria.
No mutations in APOL3 have been as-
sociated with an immunodeficiency, so it is
unknown if APOL3 makes a nonredundant
contribution to immunity. Loss-of-function
mutations in human genes involved in pro-
duction of, or response to, IFN-g chiefly lead
to increased susceptibility to mycobacterial
infections, but also to increased suscepti-
bility to Salmonella ( 13 ), an organism lysed


Rethinking immunology

An interferon-g–induced apolipoprotein lyses bacterial

membranes in the cytoplasm of host cells

Department of Microbiology and Immunology, Weill
Medical College of Cornell University, New York, NY, USA.

Cytokine release
In response to bacterial
infections, activated
lymphocytes secrete IFN-g.

Lysis of bacterium
Once the bacterium is inside the
cell, APOL3 acts as a detergent to
dissolve inner bacterial membranes,
which kills the bacteria.

Production of APOL3
Epithelial cells, endothelial cells, and fibroblasts
induce expression of APOL3 in response to IFN-g.



Dissolving bacteria
Upon detection of a bacterial infection, interferon-g
(IFN-g)-induced expression of apolipoprotein L3
(APOL3) in epithelial and endothelial cells, and
fibroblasts, protects these cells from invading bacteria.

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