Download linking the innate and adaptive immune systems

© 2007 Nature Publishing Group http://www.nature.com/natureimmunology
M E E T I N G R E P O RT
Probing the ‘labyrinth’ linking the innate
and adaptive immune systems
Peter D Katsikis, Stephen P Schoenberger & Bali Pulendran
A June 2007 meeting of immunologists in Crete focused on the intricate interconnections between the innate and
adaptive immune systems and their implications for host defense against pathogens.
T
he 2nd International Conference on
Crossroads between Innate and Adaptive
Immunity was held 17–22 June 2007 in Crete,
Greece. This conference brought together leading international scientists from the areas of
innate and adaptive immunity with the purpose
of promoting more scientific exchange between
these fields. The workshop, which we organized
with the support of Aegean Conferences, was
the follow-up to the successful 1st International
Crossroads Conference held on Rhodes in 2005.
The limited number of participants, kept below
100, together with a diverse conference program, allowed extensive interactions and ample
opportunities for scientific and social interactions. The program of this meeting included
sessions on innate immune sensing; dendritic
cells (DCs) and immune regulation; T cells and
memory; innate immunity; molecular control
of immunity; T cells, B cells, natural killer (NK)
cells and antigen-presenting cells; ‘sights and
sites’ of immunity; and regulating immunity.
A chief recurring theme of this conference
was the duality present from the very earliest
stages of the immune response involving a constant and delicate balance between proinflammatory and anti-inflammatory elements acting
in concert to ensure the delivery of the most
effective and beneficial response to pathogens
Peter D. Katsikis is in the Department of
Microbiology and Immunology, Drexel University
College of Medicine, Philadelphia, Pennsylvania
19129, USA. Stephen P. Schoenberger is in The
Laboratory of Cellular Immunology, La Jolla Institute
for Allergy and Immunology, La Jolla, California
92037, USA. Bali Pulendran is with the Emory
Vaccine Center, Department of Pathology, Emory
University, Atlanta, Georgia 30329, USA.
e-mail: [email protected]
and tumors while simultaneously containing and limiting potential damage to the host.
Examples of this duality of immune regulation can be found at the level of key cell types,
such as DCs, that can not only initiate immune
responses but also regulate them through control of inflammation. Inflammatory stimuli
delivered through Toll-like receptor (TLR)
signaling have long been known to enhance
immune responses, but emerging evidence
shows that TLRs can also induce anti-inflammatory signals. Such signals can directly affect
the pro- or anti-inflammatory activity of cells
whose functions lie squarely at the ‘crossroads’
of innate and adaptive immunity, such as
DCs, NK cells and NKT cells, causing changes
through epigenetic modifications and posttranscriptional regulation.
Sensing pathogens in many ways
A main theme of the meeting focused on how
the innate immune system senses viruses, bacteria, fungi and parasites and how this information is integrated into adaptive immune
responses. The complexity of TLR signaling
was emphasized by data showing that TLRs are
differentially expressed on distinct subsets of
monocytes, myeloid DCs, plasmacytoid DCs,
B cells and NK cells (Sefik Alkan, Baltimore,
USA). Furthermore, Alkan presented evidence
on TLR crosstalk and showed that TLRs can
act in a synergistic or additive way1. Given the
critical functions of TLRs and other innate
immune receptors in pathogen sensing and
the modulation of adaptive immunity, there
is a growing expectation that such receptors
could be harnessed in the induction of vaccineinduced immunity. Indeed, newly identified
compounds, obtained by screening of a small
molecule library, can act as potent adjuvants
NATURE IMMUNOLOGY VOLUME 8 NUMBER 9 SEPTEMBER 2007
and enhance both antibody and CD4+ T cell
responses (Jeffrey Ulmer, Emeryville, California,
USA). The rationale for pursuing TLR ligands
as vaccine adjuvants was supported by Bali
Pulendran (Atlanta, USA), who showed that
the highly successful, empirically derived yellow
fever vaccine 17D mediates its immunogenicity
by signaling through multiple TLRs2. This suggests that vaccine adjuvants that activate specific
combinations of TLRs may provide synergistic
activation of innate immunity to achieve the
magnitude and duration of the antigen-specific
B cell and T cell responses obtained with highly
successful empirical vaccines.
TLRs were not the only pathogen-sensing
machinery of the innate immune system
discussed at this meeting. Yvette van Kooyk
(Amsterdam, The Netherlands) presented data
on innate immune sensing by C-type lectin
receptors and the importance of such receptors in cell-cell interactions. DCs have differential expression of the C-type lectin receptors
MGL and DC-SIGN; this may be dictated by
the environment or site at which these DCs are
located. This is an important aspect of sensing pathogens, as DC-SIGN recognizes Lewis
antigen and high-mannose structures found
on many pathogens, whereas MGL recognizes
O-glycan structures found on tumors and helminthes. Location, therefore, may ‘instruct’
DCs to express the appropriate sensors for the
pathogens most likely to be encountered at
that site. In terms of cellular interactions and
C-type lectins, neutrophils and DCs interact by means of cytokine production, which
results in increased expression of Lewis antigen by neutrophils that in turn bind DC-SIGN.
Activated neutrophils can mature DCs by such
lectin receptor engagement and the production of tumor necrosis factor. Another cellular
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© 2007 Nature Publishing Group http://www.nature.com/natureimmunology
M E E T I N G R E P O RT
The charms of Cretan sun, sky and water were on display at the 2nd International Conference on
Crossroads between Innate and Adaptive Immunity.
interaction has been suggested by the finding
that MGL can bind CD45 on effector T cells,
preventing cell death3. This suggests that MGLexpressing DCs may be regulating the activation-induced death of effector T cells and thus
may regulate the contraction phase of the T cell
response. In addition to pathogen sensing by
antigen-presenting cells, NKT cells also have
two distinct pathways for sensing the presence
of bacteria in their environment. One involves
the direct recognition of CD1d-bound bacterial glycolipids using their invariant TCR, and
the other is through activation by interleukin
12 (IL-12) and IL-18 produced by antigen-presenting cells that are stimulated by bacterial or
viral TLR ligands (Mitch Kronenberg, La Jolla,
USA)4. Ubiquitous sphingomonas Gram-negative bacteria are unique in containing α-linked
glycosphingolipids that are ligands for both
mouse and human NKT cells, and the spirochete Borrelia burgdorferi has diacylglycerol
antigens with α-linked sugars that are also recognized by their invariant TCR. Thus, there was
a clear message that innate sensing of pathogens
occurs not only through TLRs on DCs but also
through a variety of other receptors expressed
on DCs and on other cells such as NKT cells.
Cellular immune system ‘conversations’
Several talks focused on the exquisite interactions that occur between different cells during an immune response. How interactions
between NK cells and DCs may influence the
outcome of immune responses to pathogens
was addressed by Alessandro Moretta (Genoa,
Italy). Immature DCs are killed by activated
NK cells, which thereby function as a ‘qual-
900
ity-control’ checkpoint for DCs that fail to
become activated in inflammatory settings.
This checkpoint could also lead to selection
of DC with the highest expression of major
histocompatibility class I and therefore ensure
optimal adaptive immune responses to pathogens. But what is the fate of NK cells recruited
to inflamed tissues? Depending on the presence
of IL-12 or IL-18, NK cells can become either
effector or helper cells, with the latter being
able to migrate back into the lymph node.
Exposure of NK cells to IL-4 or IL-12 generates NK cells that, when cultured together with
DCs, can modulate the polarization of naive
T cells. Thus, such NK cells can participate in
the T helper type 1 (TH1)–TH2 development
of CD4+ T cell responses.
The critical importance of innate mechanisms in defense of the host against pathogens
is emphasized by the fact that these invaders
have evolved exquisite strategies to subvert
innate immune function. For example, murine
cytomegalovirus targets DCs early during infection and selectively downregulates costimulatory ligands on the DC (Edith Janssen, La Jolla,
USA). DCs infected with this virus are less
able to prime CD8+ T cells, and this is mediated in part by interactions between the T cell
inhibitory receptor PD-1 and its ligand PD-L1.
Although innate immunity is thought to be
critical for the initiation of immune responses,
emerging evidence suggests a function for it in
providing instructive cues even after the adaptive immune response is underway. This was
emphasized by Peter Katsikis (Philadelphia,
USA), who reported that in contrast to the conventional view that costimulation is required
solely for priming T cells, antiviral memory
CD8+ T cells also require B7-CD28 signals
to mount a maximal response and rapidly
clear viruses. B7-CD28 signaling may also be
required late during the effector phase of the
antiviral CD8+ T cell response to promote the
survival of effector cells.
Finally, the application of two-photon
imaging techniques to visualize the intricate cellular interactions that occur during an immune
response was discussed by Ronald Germain
(Bethesda, USA)—who choreographed immune
cells ‘dancing’ to Cretan music. Lymph nodes
contain highly structured networks consisting
of fibroblastic reticular cells. The movement of
T cells along these fibers facilitates their interaction with DCs that are also associated with the
fibroblastic reticular network. The fibroblastic
reticular DC network and its associated chemokines define the T cell and B cell areas of the
lymph node. Exciting data were also presented
on B cell–DC interactions in the lymph node5.
Antigen-specific interactions occur between B
cells and DCs and, after contact, B cells flux calcium. These B cells pick up antigen from DCs
and present it to CD4+ T cells. These complex
interactions between DCs and B cells can take
a rather nasty turn in malignancies. Can DCs
act as prosurvival elements in immunological malignancies? This question was posed by
Kelvin Lee (Buffalo, USA), who analyzed the
expression of CD28 on plasmacytomas and
its potential survival enhancement effect. The
CD28 ligands are presumably provided by DCs,
which were shown to support the survival of
germinal center B cells and plasma cells. DCs
are selectively recruited to myelomas, where
they may inhibit proliferation but enhance survival, as shown by the finding that DCs cultured
together with myeloma cells make indoleamine
2,3-deoxygenase, which can inhibit immune
responses. Thus, the B cell–DC crosstalk can
be beneficial by supporting immune responses
but also can have a much less desirable function
in B cell malignancies.
Balancing gut immunity versus tolerance
A second theme of the meeting was how the
immune system controls inflammation in the
intestine while maintaining effective immunity
against pathogens. This is a particularly challenging problem, as the intestinal environment
contains a rich flora of commensal bacteria and
is also replete with various types of DCs and
macrophages that express TLRs. So what keeps
us all from dying of sepsis? The central importance of DCs in this environment was graphically demonstrated by Ronald Germain, who
showed images of ‘balloon body’ extensions of
DCs that protrude through small bowel epithelium and into the lumen, presumably to sam-
VOLUME 8 NUMBER 9 SEPTEMBER 2007 NATURE IMMUNOLOGY
© 2007 Nature Publishing Group http://www.nature.com/natureimmunology
M E E T I N G R E P O RT
ple pathogens or their products. Furthermore,
Brian Kelsall (Bethesda, USA) presented data
on the function of DCs in the Peyer’s patches in
inducing immunity against reoviral infections,
probably by a TLR-independent mechanism
involving type I interferon6, thus emphasizing the importance of these cells in mediating
immunity in the gut.
In contrast, two talks focused on how immunity in the gut may be controlled to prevent self
reactivity. Central tolerance mechanisms typically involve medullary thymic epithelial cells,
which use endogenously expressed peripheral
tissue antigens to delete self-reactive thymocytes. The prevailing model for the induction
of peripheral tolerance involves cross-presentation of tissue antigens by quiescent DCs. Lymph
node stromal cells present endogenously
expressed peripheral tissue antigens to T cells
to induce primary activation and subsequent
tolerance among CD8+ T cells (Shannon Turley,
Boston, USA). TLR signaling may regulate the
expression of PD-1 ligand on lymph node
stromal cells and thus participate in peripheral
tolerance. Lymph node stromal cells, therefore,
seem functionally akin to medullary thymic
epithelial cells and provide a direct strategy for
purging the peripheral repertoire of self-reactive
T cells7. Furthermore, Bali Pulendran presented
evidence of a newly identified subset of macrophage in the lamina propria that has constitutively high expression of IL-10 and induces T
regulatory cells. These macrophages also inhibit
the induction of TH-17 responses by DCs in the
same lamina propia microenvironment. Thus,
self-tolerance versus immunity in the intestine
may be orchestrated by the dynamic interaction
between distinct subsets of antigen-presenting
cells and stromal cells.
But what keeps TLRs from firing excessively
in response to commensal organisms, resulting
in sepsis? The involvement of TLRs in acute
inflammation in the colon was investigated with
a model of acute colitis, in which inflammation
and disease occur in a T cell–independent way
(Eyal Raz, San Diego, USA). Paradoxically, in
this model, triggering of TLR9 inhibits dextran sodium sulfate–induced colonic inflammation by a mechanism involving the release
of type I interferon. Thus, mice deficient in the
interferon-α/β receptor develop more severe
colitis than wild-type mice do after the induction of experimental colitis. These results indicate that TLR9-triggered type I interferon has
anti-inflammatory functions in this model of
colitis; they also emphasize the important protective function of type I interferon in intestinal homeostasis and suggest that strategies
for modulating innate immunity may be of
therapeutic value for the treatment of intestinal
inflammatory conditions8.
‘Tuning’ responses with innate immunity
Consistent with the theme of the conference, a
series of presentations addressed the adaptive
response and ways that it can be influenced by
innate immunity. With data relevant to many
published studies, John Harty (Iowa City, USA)
showed that the surface phenotype of ‘memory’
CD8+ T cells produced in an acute infection
model is directly influenced by the frequency of
naive precursors present at the time of priming9.
Using titrated doses of monoclonal transgenic
T cells, Harty demonstrated that with high
input numbers, most memory CD8+ T cells
generated are CD127loGrB+IL-2loCD62Llo,
in contrast to the response generated when
precursor frequencies are closer to that of the
endogenous repertoire. Notably, the protective
immunity, kinetics and phenotype of the memory response generated by high and low input
with a listeria infection model was the same.
John Wherry (Philadelphia, USA) showed
that antiviral CD8+ T cells from chronic viral
infection have less homeostatic proliferation
because of their low expression of the IL-7
receptor and the Bcl-2 antiapoptosis protein10.
The maintenance of such cells during chronic
infection is antigen dependent. The numbers
of in vivo chronically antigen-stimulated CD8+
T cells are regulated by apoptosis mediated by
the cell surface death receptor Fas, whereas the
reactivation defect of these cells may be dependent on the proapoptotic cell surface receptor
TRAIL (Christine Bucks, Philadelphia, USA).
Data were presented suggesting the existence
of a previously unknown binding partner for
B7-1–B7-2 expressed on CD8+ T cells involved
in regulating their early survival after priming
(Stephen Schoenberger, La Jolla, USA). This
conclusion is based on observations of discrepancies between the fate of CD8+ T cells primed
in the absence of B7-1–B7-2 and that of CD8+
T cells primed in the absence of CD28 and the
T cell inhibitory receptor CTLA-4.
Epigenetics and microRNA
The regulation of immune responsiveness by
post-transcriptional and epigenetic mechanisms was addressed by many speakers. Martin
Turner (Cambridge, UK) discussed the function of microRNA in immune responses11. The
microRNA miR-155, encoded by the B cell intergration cluster (BIC), is upregulated on stimulated B cells and CD4+ T cells, and BIC-deficient
mice fail to mount a protective response after
vaccination and succumb to oral salmonella
infection. Both antibody priming and T cell
priming are defective in these mice, and their
DCs have less T cell stimulatory capacity.
Finally, BIC seems to regulate TH1-TH2 development, as immune responses in BIC-deficient
mice are skewed toward TH2. The amount of
NATURE IMMUNOLOGY VOLUME 8 NUMBER 9 SEPTEMBER 2007
switched immunoglobulins is lower and affinity maturation is impaired in BIC-deficient B
cells. However, this happens even though class
switching and somatic mutations occur at the
DNA level, suggesting that a single microRNA
can be important in the post-transcriptional
regulation of B cell responses.
In addition to post-transcriptional control of
cells, epigenetic changes may also contribute to
function and differentiation. Indeed, epigenetic
modifications determine the functional defects
of ‘helpless’ CD8+ T cells, as shown by Hao Shen
(Philadelphia, USA). Histone acetylation of the
interferon-γ locus is lower in ‘helpless’ CD8+ T
cells, and restoration of acetylation restores
the survival and function of ‘helpless’ CD8+
T cells12. These presentations brought into
focus the idea that the function of cells can be
determined at multiple levels and that such epigenetic and post-transcriptional mechanisms
must be kept in mind in studies of the immune
response.
This crossroads meeting brought into focus
the bigger picture of the extensive interactions
and crosstalk between cells of the adaptive
and innate immune systems. The complexity of these interactions and of pathogensensing and recognition, and the fine balance
of the outcome of these interactions, were
emphasized again and again throughout the
meeting. The meeting thus fulfilled its goals
of bringing together investigators working in
each of these diverse fields and stimulating
meaningful discussion and exchange of ideas.
The meeting closed with attendees and organizers performing Greek dances, and with the
promise that the 3rd International Conference
on Crossroads between Innate and Adaptive
Immunity, planned for 2009, will continue the
tradition of scientific stimulation and energy
the attendees enjoyed during the previous two
meetings.
COMPETING INTERESTS STATEMENT
The authors declare no competing financial interests.
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