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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 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 899 © 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. 1. Ghosh, T.K. et al. Cell. Immunol. 243, 48–57 (2006). 2. Querec, T. et al. J. Exp. Med. 203, 413–424 (2006). 3. van Vliet, S.J., Gringhuis, S.I., Geijtenbeek, T.B. & van Kooyk, Y. Nat. Immunol. 7, 1200–1208 (2006). 4. Nagarajan, N.A. & Kronenberg, M. J. Immunol. 178, 2706–2713 (2007). 5. Qi, H., Egen, J.G., Huang, A.Y. & Germain, R.N. Science 312, 1672–1676 (2006). 6. Johansson, C. et al. J. Exp. Med. 204, 1349–1358 (2007). 7. Lee, J.W. et al. Nat. Immunol. 8, 181–190 (2007). 8. Katakura, K. et al. J. Clin. Invest. 115, 695–702 (2005). 9. Badovinac, V.P., Haring, J.S. & Harty, J.T. Immunity 26, 827–841 (2007). 10. Shin, H., Blackburn, S.D., Blattman, J.N. & Wherry, E.J. J. Exp. Med. 204, 941–949 (2007). 11. Rodriguez, A. et al. Science 316, 608–611 (2007). 12. Northrop, J.K., Thomas, R.M., Wells, A.D. & Shen, H. J. Immunol. 177, 1062–1069 (2006). 901