DISCUSSION FORUM
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Response to Cohn: The Immune System Rejects
the Harmful, Protects the Useful and Neglects
the Rest of Microorganisms
Z. Dembic
Summary
Department of Oral Biology, University of Oslo,
Oslo, Norway
Received 25 March 2004; Accepted 6 April 2004
Correspondence to: Dr Z. Dembic, University of
Oslo, Department of Oral Biology, PB 1052
Blindern, N 0316 Oslo, Norway. E-mail: zlatko.
dembic@odont.uio.no
The immune system is seen as a guardian of tissue integrity. It would analyse the
extent and quality of damage and respond adequately. If no ill effects were
found, the system would ignore disturbance, but if beneficial effects were found,
it could protect certain microorganisms (establishing commensalism), perhaps
via regulatory cells. The Integrity hypothesis proposes three basic groups of
intercellular signals for cells of all tissues and assumes that they govern communication between dendritic cells, T cells and B cells. Signal-1 would be the main
information source resulting with generation of intracellular mediators that are
bound to travel into the nucleus to achieve reaction. Signal-2 represents the
generation of additional signal transducers representing a modifier at the level of
cytosol. And, signal-3 would be a modifier at nuclear level, perhaps guarding
accessibility to chromosome or genetic locus.
The paper by M. Cohn describes two decisions that the
immune system should make in response to pathogens.
The first decision is the sorting of the repertoire, and the
second is about immune response’s magnitude and class,
all for combat reasons against pathogens. On what basis
can one separate these two decisions? Is not sorting of a
repertoire linked to the magnitude? For example, sortedout elements (cells) require signals that surpass certain
threshold of magnitude in order to react (and be sorted).
A magnitude of a response seems to be intrinsic to sorting
decision! On the other hand, the decision about the class
of the response could stand very well on its own. However,
there might be a different solution to this problem.
There is a model in which the immune system has three
decisions to make and is helped by a three-signal cellular
activation mechanism that operates for communication
purposes among the cells [1–4]. The concept involves the
immune system as a guardian of tissue integrity. The
integrity hypothesis differs from the Danger [5–7] and
the Pattern recognition model [8, 9] in that the immune
system is thought to think in terms of being able to discern
three conditions and consequently make three types of
responses. The immune system would reject the harmful,
protect the useful and neglect the rest of the microorganisms that surround us or live in our bodies.
Integrity incorporates three basic intercellular communication signals and assumes that communication between
dendritic cell (DC), T cell and B cell is a social affair that
allows thinking and making intelligent decisions at the
microscopic level. The analogy with the neural tissue is
clear: one neuron cannot think but a group of neurons
can. In brief, structural disruption (a slight damage) of any
tissue provides a message to T cells and B cells (via DC)
that something is happening (alert). However, if there were
an associated message that the function of the tissue has
been compromised as well, the immune response would
ensue. On the other hand, should this functional-damage
evidence be lacking, the immune system would assume
that the matter should be either neglected or considered
for its usefulness. For the latter, if useful for the function
of a tissue, the immune response would become a protection of the antigenic carrier (we could envisage this as
some kind of active tolerance). Maybe, this is the reason
why some vitamin K-producing bacteria become protected
in the gut. The protection of useful commensalisms would
be of selective advantage and would therefore counteract
disadvantage provided by pathogenic mimicry of such
signals. Namely, a pathogen by definition would always
bring functional disability to tissues, whereas benefactor
would improve it. The signal of usefulness cannot be
# 2004 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 60, 3–5
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Z. Dembic
4 Discussion Forum
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hijacked by pathogens because usefulness and harmfulness
are mutually exclusive.
The alert signal can be provided by (exogenous) danger
or pattern recognition receptors, but it might still go one
way or another, depending on the functional-damage
signal, which in turn depends on 30,000 or so (genetic)
reasons of how one measures tissue integrity. This variability keeps in check the T repertoire and B repertoire that
need this clearance in order to reject the intruder (via CD8
T-cell cytotoxicity or T-B response and secretion of Ig) or
protect by generating regulatory cells (and perhaps by
secreting inhibitory cytokines). It is a hard decision for an
individual immune system, because it may seem that it is
the final one regarding that particular epitope, i.e. there is
no way back to restore rejection capability until that
(suppressor) cell (or a clone) is alive. Therefore, this is not
a real loss of a clone bearing a paratope in the repertoire
against pathogens, but a functional loss in the rejection
repertoire. In other words, if all tolerance fails (clonal
deletion – central and peripheral – and perhaps anergy),
suppressor response for certain epitopes would protect the
carrier of this antigen for the rest of the guardian’s (suppressor cell) life. I propose that this function (protection)
has been selected from the mechanisms that guard the
integrity of tissues. In such a way, the last resort to combat
autoreactivity and its detrimental consequences would be
the protection of tissues by, for example, regulatory T cells
or soluble factors making particular tissue (or part thereof) a
truly immunologically privileged site. From such function,
protection of some useful microorganisms could have been
evolutionarily selected.
It may therefore make sense to propose that DC need at
least two signals to become activated (matured) in order to
activate naı̈ve or resting T cells. One of these signals must
be independent of the recognition ability of past infections
[pattern recognition, i.e. Toll-like receptor (TLR), mannose receptor, etc.], which increases the number of minimal signals required for the activation of immune response
stimulatory DC to three. The signal-1 and the signal-2 for
DC could be additive or synergistic. They could be even
transmitted through different members of the same family
of receptors. For example, TLR can provide both the
signal-1 and the signal-2 for DC. The signal-3 for DC
could be the tissue damage (disruption of integrity). The
signal via TLR in DC can be separated into two suboptimal signals that can be dissociated, perhaps similarly as it
was shown to be the case with TLR2 signalling [10]. In
TLR2-signalling case, suboptimal binding of TLR2 ligand
caused DC to provide presentation of peptide on major
histocompatibility complex (MHC) class II molecules, but
without upregulation of costimulatory molecules. The
latter were upregulated only with optimal TLR2 concentration of ligands. Thus, stimulation of naı̈ve T cells [via
MHC peptide/T-cell receptor (TCR) interaction; the signal-1 for T cells] can be separated from costimulation of
T cells (via, for example, B7/CD28 interaction; the signal-2
for T cells) at the level of dendritic cell!
There is more evidence that fit with such a proposal.
A support comes from a report that cross-linking of TLR4
by lipopolysaccharide (LPS) is usually required to signal
downstream in macrophages [11]. In contrast, binding of
LPS under suboptimal conditions does not lead to downstream
signalling. I would argue that it still might endow DCs to
provide the signal-1 for T cells (stimulation). Moreover, other
TLR4 ligands like HSP act on TLR4 by enhancing stimulatory
effects of otherwise substimulatory concentrations of LPS
[12]. These could additionally endow DCs to provide the
signal-2 for T cells (costimulation). Lastly, there is evidence
that intracellular TLR-signalling cascade can be synergistically triggered by ligands of TLR2 and TLR9 or TLR4
and TLR9 under suboptimal conditions [13]. All these results
support the idea about two-level TLR signalling in antigenpresenting cells. The first level would result only with the
stimulation of naı̈ve T cells. This would be achieved by the
signal-1 for DC (a suboptimal concentration of the ligand)
and would provide DC with a source of protein that could be
processed and presented on MHC molecules. The second
level of TLR signalling would ensue under optimal ligand
concentration. Thus, if provided by the signal-2 at the same
time, the DC would upregulate costimulatory molecules (i.e.
B7, ICOSL and PD-L2). The signal-1 and the signal-2 for
DC would be interchangeable within the TLR family of
molecules. Perhaps other pattern recognition receptors
might also contribute in a similar way. Thus, all this would
lead to naı̈ve (and resting memory) T-cell activation, provided the signal-3 for DC is also present (in terms of tissue
damage). Without this tissue disruption, no T-cell activation
(in terms of concomitant proliferation) and no immune
response would take place [4].
Therefore, the immune response in terms of rejection
would require the signal-1, -2 and -3 at the level of DC.
We now have at least three other conditions to consider that
could give different information to DC (and subsequently
T cells and B cells):
(A) Tissue damage (as the signal-3) in combination with the
signal-1 (without the signal-2).
(B) The signal-1 and the signal-2 without the signal-3.
(C) The signal-1 alone.
After DC interacts with T cell under the option A, it
would yield a regulatory type of a T cell (in other words,
the signal given to naı̈ve T cell to proliferate and become
an effector might seem a bit confusing, because not all the
necessary molecules would have been present). The T cell
might be stuck in a limbo and, by moving into tissues
without developing into killer or helper effectors, would
shield the target and thereby prevent access to them. In
addition, secreting inhibitory cytokines by such T cells
might be the function related to a difference in quality of
the signal-3 that has been previously transferred via DC.
# 2004 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 60, 3–5
Z. Dembic
Discussion Forum 5
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The option B would yield anergy (with interesting
possibilities, if the signal-3 would be introduced at some
later point in time).
Lastly, the option C (or the signal-1 alone) would yield
peripheral clonal deletion (this should be passive tolerance,
via programmed cell death).
Why would a combination of the signal-1 and the
signal-3 yield regulatory cell rather than a deletion (apoptosis)? It could be envisaged that the signal-3 regulates
accessibility to DNA; thus, apoptotic signal-1 with larger
access to genomic resources (the signal-3) might allow a
selection process by which a cell might find a way to
survive and escape programmed cell death. The third
signal (or the integrity disruption signal) might have a
different quality in terms either of a magnitude or
destroyed particular function of a damaged tissue, all of
which can provide different mediators in DC as a consequence of such signal. This can lead to a difference in a
class of the response.
Thus, the signal-3 would measure the quantity of tissue
damage and translate it into a quality difference (class of
the response). Similarly, the signal-1 and the signal-2
would measure a quantity of structural change in tissues
and transform it in logic of the immune response: rejection
or protection or neglection or indefinite waiting for a
decision. In addition, some of these mechanisms might
be utilized for homeostatic purpose. Perhaps, the true
function of the immune system is reflected in immunocyte
development, because T-cell and B-cell clones undergo
processes that delete harmful, protect (positively select)
useful and disregard the rest of the cells during ontogeny.
References
1
2
3
4
5
6
7
8
9
10
11
12
13
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Dembic Z. Do we need integrity? Scand J Immunol 1996;44: 549–50.
Dembic Z. Immune system protects integrity of tissues. Mol Immunol 2000;37:563–9.
Dembic Z. About theories and the integrative function of the
immune system. The Immunologist 2000;8:141–6.
Dembic Z. The function of Toll-like receptors. In: Rich T, ed. Toll
Receptors. Landes Bioscience/Eurekah.Com and Kluwer Academic/
Plenum, Gorgetown, 2004: 1–38 (chapter 1).
Matzinger P. Tolerance, danger, and the extended family. Annu Rev
Immunol 1994;12:991–1045.
Matzinger P. Essay 1: the Danger model in its historical context.
Scand J Immunol 2001;54:4–9.
Matzinger P. The danger model: a renewed sense of self. Science
2002;296:301–5.
Janeway Jr CA. Approaching the asymptote? Evolution and revolution
in immunology. Cold Spring Harb Symp Quant Biol 1989;54:1–13.
Medzhitov CA, Janeway Jr R. Introduction: the role of innate
immunity in the adaptive immune response. Semin Immunol
1998;10:349–50.
Schjetne KW, Thompson KM, Nilsen N et al. Link between innate
and adaptive immunity: Toll-like receptor 2 internalizes antigen for
presentation to CD4þ T cells and could be an efficient vaccine
target. J Immunol 2003;171:32–6.
Latz E, Visintin A, Lien E et al. Lipopolysaccharide rapidly traffics
to and from the Golgi apparatus with the toll-like receptor
4-MD-2-CD14 complex in a process that is distinct from the
initiation of signal transduction. J Biol Chem 2002;277:47834–43.
Wallin RP, Lundqvist A, More SH, von Bonin A, Kiessling R,
Ljunggren HG. Heat-shock proteins as activators of the innate
immune system. Trends Immunol 2002;23:130–5.
Equils O, Schito ML, Karahashi H et al. Toll-like receptor 2 (TLR2)
and TLR9 signaling results in HIV-long terminal repeat transactivation and HIV replication in HIV-1 transgenic mouse spleen
cells: implications of simultaneous activation of TLR on HIV replication. J Immunol 2003;170:5159–64.