Immunity to infection

Editorial overview
lessons on the immune response from the war on bugs

Michael J. Bevan and Alan Sher

Howard Hughes Medical Institute, University of Washington, Seattle and National Institutes of
Health, Bethesda, USA

Current Opinion in Immunology 1993, 5:477-478

The diversity of pathogens in our environment is enor-
mous. Ranging from simple genomes to multicellular
worms, these parasites push the defenses of mammalian
hosts to their absolute limit. Studying the host response
to infectious agents teaches us everything about the im-
mune system as it was this onslaught by pathogens that
drove its evolution. While research on chemically defined
antigens (e.g. hapten-carrier conjugates) has been nec-
essary in defining the specificity of immune recognition
and mechanisms of cellular interaction involved in this
process, such model systems tell us little about the func-
tional significance of immune responses, their orchestra-
tion and diversification within the host. From the days
of Ehlrich and Metchnikoff, studies on the immunology
of infection have provided us with major insights con-
cerning these more physiological aspects of the immune
response. As is evident from the excellent reviews as-
sembled in the current issue, the ongoing and never
completed ‘war on bugs’ continues to provide lessons
which delve into the basic functions of the immune
system. In several areas, such as CD4+ -subset determi-
nation, cytokine research, and the cell biology of anti-
gen processing and presentation, studies on infectious
disease models have emerged into the forefront of their
fields.
An important new tool now being incre&ngly applied
to the study of host-pathogen models is the genetically
engineered ‘knock-out’ mouse in which specific elements
of the immune system are deleted. As summarized in the
opening chapter by Doherty (pp 47!+483), a rapidly ex-
panding body of information is emerging from studies on
these animals. Ironically, while initially conceived as an
approach for confirming the in zkjo role of the immune
effector and regulatory functions, ‘knock outs’ are teach-
ing us more about the redundancies of the immune sys-
tern. Such redundancies in effector mechanisms are eti-
dent in many of the functions discussed, including the vi-
ral models highlighted by Doherty, Mycobucteriu (Orme,
pp 497-502), Listeriu (Bancroft, pp 503-510) and Tox-
oplasma gondii (Subauste and Remington, pp 532-537)
where it is clear that CD4+, CD8+ T lymphocytes and
natural killer (NK) cells have overlapping and often mu-
tually compensating roles in host resistance.
The study of the functional significance of CD4+ T-cell
subsets and their associated cytokines remains a domi-
nant theme in the work summarized this year. The role
of T helper type 1 (Thl) and T helper 2 (Th2) subsets
in resistance has now been extensively analyzed in many
microbial systems and in particular in the leishmania
(Reed and Scott, pp 524-531) and helminth (Wilson,
pp 53%547) murine parasite models. Of recent inter-
est has been the extension of these studies into hu-
man disease (Modlin and Nutman, pp 511-517) where,
despite the added complexities, many aspects of the
Thl/Th2 functional dichotomy appear to apply. A cur-
rent emphasis in both the mouse and human studies is
the crossregulatory functions of cytokines produced by
Th cells and their role in the control of infection and
disease. These regulatory cytokines have now replaced
suppressor cells as the most favoured explanation of im-
munological downregulation in infection.
A question now emerging as central in the immunoreg-
ulation of infection concerns the mechanism by which
different host-pathogen encounters trigger the expan-
sion of different CD4+ subsets. An explanation favoured
by many is that the early cytokine environment plays
a critical role in determining the outcome of this in-
teraction and that the initital encounter between the
pathogen and non-specific resistance elements (e.g. NK
cells, macrophages, mast cells, y6 T cells) may provide
the source of regulatory cyotkine. The ability of certain
intracellular bacteria and protozoa to stimulate IFN-)I pro-
duction from NK cells (reviewed by Bancroft) has now
been proposed as an important mechanism determining
the differentiation of Thl -cell responses associated with
these infections (Reed and Scott). A newly characterized
cytokine, IL-12, has recently been shown to play a U-L-
cial role in the stimulation of IFN-y production by NK
cells (Bancroft) as well as the determination of Thl-
subset differentiation in response to Leishmania infec
tion (Reed and Scott) and may develop into a powerful
tool for manipulating the immune response to pathogens
to the benefit of the host [ 11.

Abbreviations
NK-natural killer; NO-nitrogen oxide; T&T helper.

@ Current Biology Ltd ISSN 0952-7915 477

Immunity to infection
Because of their crucial role as an accessory cell in
the initiation of both T-cell and NK-cell responses, in-
creasing attention is being paid to macrophages and
the signals induced within them by different pathogens
and their products. As emphasized by James and Nacy
(pp 518-5231, the activated macrophage is a major effec-
tor cell in host resistance to a variety of intracellular as
well as extracellular pathogens and its function in limiting
parasite survival is closely regulated by cytokines, many of
which have corresponding suppressive effects on T lym
phocyte responses. Whereas in the mouse toxic nitrogen
oxide (NO) metabolites appear to be the major media-
tors by which macrophages, as well as several other types
of effector cell activated by cytokines, kill the pathogens,
this mechanism has yet to be demonstrated in humans.
The search for the postulated human NO homologue rem
mains an important challenge for macrophage biologists
studying host resistance.
The complex interplay between host cell and pathogen
is particularly well illustrated with pathogenic intracel-
lular bacteria that cause enteric diseases, leprosy and
tuberculosis (Pamer, pp 492496). Signal transduction
pathways of the host cell are exploited and interdicted
by the pathogen which has also evolved to use the host
cytoskeleton. In response to the life style of these bacte-
ria, the host may have developed specialized antigen-pre-
sentation pathways.
While AIDS and mycobacterial infections present ever-
growing threats to populations in developed countries,
malaria which kills over a million children annually re-
mains a major scourge in many Third World countries.
As in the Mycobacteriu (discussed by Orme), the emer-
gence of drug resistance organisms poses a special global
hazard and underscores the urgent need for effective vac-
cines for both pathogens,
As discussed by Long (pp 54%556) and Kaslow
(pp 557-565) several highly promising vaccine candi-
dates have recently emerged from studies on immunity to
malaria. In the case of immunization against blood stages,
encouraging results have been obtained in experimental
models by vaccinating with individual parasite proteins or
recombinant epitopes and, in humans exposed to Plas-
modium falciparum, with a hybrid vaccine consisting
of peptides from three different erythrocytic-stage anti-
gens. While the mechanisms underlying the induction
of resistance by these vaccines remain to be defined,
great progess has been reported in characterizing both
specific and non-specific cytokine responses induced by
blood-stage infection and their associations with pathol-
ogy or host immunity. A novel and highly feasible ap-
proach for reducing malaria infection, is the inductior
of transmission-blocking immunity. The strategy of thh
form of immunization is to eliminate sexual stages of the
parasite which develop in the mosquito, thereby prevent-
ing infection of the mammalian hosts. As summarized by
Kaslow, experimental vaccines that induce high levels 01
biologically active antibodies have now been developed
against sexual stage recombinant antigens and are ready
for testing in man.
Vaccine development remains the major immunological
approach to disease prevention in populations. Never-
theless, the advent of sophisticated new technologies
for manipulating and substituting immune responses,
has spawned a flurry of interest in the development of
immunotherapeutic approaches for use in individual pa-
tients. In the important area of AIDS treatment and man-
agement, a wide variety of strategies are being tested for
conferring resistance against the HIV virus as well as op-
portunistic pathogens. A highly promising approach sum-
marized by Riddell, Gilbert and Greenberg (pp 484-491)
is the transfer of CD8+ viral-specific cytotoxic T lympho-
cyte clones, which in clinical trials on immunosuppressed
bone marrow recipients has provided significant protec-
tion against opportunistic infection with cytomegalovirus.
While the application of this technology to the control of
the HIV virus poses a much greater challenge, this work
firmly establishes the feasibility of adoptive immunother-
apy of infection in immunocompromised patients and
should encourage the development and testing of similar
technologies aimed at specific immune reconstitution.
As always, the continuing ‘hand-shake’ between funda-
mental immunology and disease research makes the
study of immunity to infection a stimulating and mutu-
ally rewarding endeavour for basic scientists and those
directly concerned with the war on bugs!
References
1. SCOTT PA: IL-12: Initiation Cytokine for Cell-mediated Im-
munity Science 1993, 260~496497.
MJ Bevan, Department of Immunology, Howard Hughes Medical Insti-
tute, LJniversity of Washington SL-15, Seattle, Washington 98195, IJSA.
A Sher, Immunology and Ceil Biology Section, Iaboratoty of Parasitic
Diseases, National Institutes of Allergy and Infectious Diseases, National
Institutes of Health, Building 4, Room 216, Bethesda, Maryland 20892,
USA