Published online before print May 12, 2006
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
* Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Japan; and
Department of Microbiology, College of Medicine, Ewha Womens University, Seoul, Korea
1Correspondence: Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita 565-0871, Japan. E-mail: mmiyasak{at}orgctl.med.osaka-u.ac.jp
ABSTRACT
The International Cytokine Society Conference 2005 was held in Seoul, Korea, October 27–31, 2005. This meeting provided the attendants an excellent forum to discuss recent advances in the biology of cytokines, chemokines, their receptors, and the receptors for innate immunity, with particular emphasis on the possibility of interfering with these systems for therapeutic purposes. We herein summarize some of the key findings discussed at the meeting.
Key Words: innate immunity • T-bet • IL-2 • IL-15 • CCR5
A pleasant Oriental atmosphere and good Korean food were the setting for the International Cytokine Society Conference 2005 in Seoul, Korea, at which the participants fully enjoyed discussing cutting-edge science over a 3 1/2-day period (October 27–31, 2005). At this meeting, recent advances in the biology of cytokines, chemokines, their receptors, and the receptors for innate immunity were addressed, with particular emphasis on the possibility of interfering with these systems for therapeutic purposes. Interesting topics in mucosal immunology were also discussed. Here, we summarize some of the key findings discussed at the meeting.
Laurie Glimcher (Boston, MA) addressed the role of a transcription factor, T-box expressed in T cells (T-bet), in Type 1 immunity. In primary T cells, T-bet transactivates the interferon-
(IFN-) gene, thereby inducing the transcription of unique gene sets that regulate T helper cell type 1 (Th1) cell migration and adhesion [1
]. Consistently, T-bet-deficient mice show impaired, activated CD4 T cell migration and are resistant to a wide range of Th1-related autoimmune diseases. T-bet can also repress commitment to the Th2 lineage by repressing Th2 cytokines, including interleukin (IL)-4 and IL-5, in T cells. Glimcher presented the novel and exciting observation that upon its tyrosine phosphorylation by a nuclear kinase, inducible T cell kinase, T-bet forms a heterodimer with the Th2-driving transcription factor GATA-3 and thereby interferes with GATA-3 binding to the IL-5 promoter DNA in vitro [2
]. Thus, T-bet controls the lineage commitment of Th1 and Th2 cells by driving genetic programs in Th1 cells and by repressing the development of the opposing Th2 cell subset. As transactivation of the IFN- gene does not require T-bet tyrosine phosphorylation, activation of the Th1 program and repression of the Th2 program by T-bet can occur separately. This finding also raises the possibility that the Th1 lineage commitment occurs as a default pathway in T cell activation.
John Sprent (La Jolla, CA) discussed the role of c cytokines, including IL-15, IL-7, and IL-2, in the survival and maintenance of CD8+ T cells with the memory (CD44hi) phenotype. Among these cells, the CD122hi, CD44hi CD8+ T cells divide intermittently and are strongly dependent on IL-15 for their survival and turnover [3
]. This cell subset shows homeostatic proliferation in IL-7–/– mice and IL-15–/– mice but not in IL-7–/– IL-15–/– mice, indicating that IL-7 can substitute for IL-15 for their turnover. In addition, this subset shows substantial proliferation in vivo when IL-2 is administered. Paradoxically, these cells also show significant proliferation when an anti-IL-2 monoclonal antibody (mAb) is given and when IL-2 and an anti-IL-2 mAb are given simultaneously. Although the mode of action remains unknown, Sprent suggested that the combination of IL-2 plus the anti-IL-2 mAb may be used successfully to expand CD8+ memory T cells in certain therapeutic setups.
Thomas Waldmann (Bethesda, MD) showed contrasting roles for IL-2 and IL-15 in the life and death of lymphocytes and proposed that IL-15 should be used preferentially over IL-2 in the treatment of cancer and as an adjuvant component of vaccines. Although IL-2 and IL-15 share receptor subunits (ß and c) and are functionally redundant in many ways, the eventual outcomes of their functions are different. IL-2 is pivotally involved in activation-induced cell death, which leads to the elimination of self-reactive T cells and thereby facilitates the induction of peripheral tolerance. By contrast, IL-15 inhibits this process. IL-15 stimulates the development of CD8+ memory T cells, but IL-2 inhibits their persistence in vivo. Studies with gene knockout (KO) mice support the idea of competitive roles for IL-2 and IL-15 in the maintenance of self-tolerance and long-lasting memory responses: IL-2–/– and IL-2 receptor 
–/– (IL-2R–/–) mice develop the lymphoid hyperplasia associated with autoimmune disorders, but neither IL-15–/– nor IL-15R–/– mice manifest lymphoid hyperplasia; rather, they show markedly reduced numbers of natural killer (NK), NKT, and memory CD8+ T cells. Waldmann also suggested IL-15 to be therapeutically promising. IL-15 transgenic mice are more resistant than wild-type to tumor cell challenge [4
], and the coadministration of vaccinia viruses expressing IL-15 with human immunodeficiency virus (HIV) vaccine vectors in mice induced long-lasting, anti-HIV CD8+ cytolytic T lymphocyte immunity, but IL-2-expressing vaccinia viruses induced only short-lived responses [5
]. However, as IL-15 is potentially dangerous because of its capacity to induce inflammatory cytokines, it may have to be functionally regulated in therapeutic set-ups. It is interesting that a humanized mAb against the IL-2Rß chain (HuMikß1) is potentially useful in this regard, and according to Waldmann, this antibody inhibits many unwanted actions of IL-15.
Warren Leonard (Bethesda, MD) presented recent data about the role of thymic stromal lymphopoietin (TSLP) in the development of inflammatory reactions in an experimental asthma model [6
]. The receptor for TSLP is a heterodimeric complex of IL-7R and a specific subunit TSLPR. Therefore, TSLP shares some redundant actions with IL-7, inducing the expansion of T and B cells when it is given to c KO mice. In addition, TSLP can induce naïve CD4+ T cells to generate the proallergic Th2 cytokines, including IL-4, -5, and -13. Using TSLPR-deficient mice, Leonard showed TSLP to have a key role, not only in promoting the proliferation of CD4+ T cells but also in generating inflammatory reactions in the lung. TSLP is thus potentially a good target for modulating inflammation in allergic diseases.
Certain viruses exploit the immune system through ingenious molecular mimicry. Phil Murphy (Bethesda, MD) presented some beautiful examples of viral mimicry of chemokines and chemokine receptors by specific herpesviruses and lentiviruses. He also discussed the biological role of CC chemokine receptor 5 (CCR5). As shown previously, individuals homozygous for the CCR5
32 mutation lack functional CCR5 and are therefore highly resistant to HIV infection. Conversely, CCR5 also appears to confer on mice resistance to West Nile virus (WNV)-induced encephalitis [7
]. Murphy showed that CCR5 and its ligand CCL5/regulated on activation, normal T expressed and secreted (RANTES) are markedly up-regulated in the WNV-infected mouse brain, and their up-regulation is associated with infiltration of the central nervous system by CCR5-expressing inflammatory cells. WNV infection of CCR5–/– mice induces an increased viral load with markedly reduced inflammatory cell infiltration of the brain, compared with WNV infection of CCR5+/+ mice, and has a rapid and uniformly fatal outcome. The adoptive transfer of activated CCR5+/+ spleen cells protects the CCR5–/– mice by inducing CCR5-dependent, protective inflammatory responses in the brain. Thus, the trafficking of CCR5+ leukocytes to the brain is apparently critical for the survival of WNV-infected animals. Murphy then investigated whether human CCR532 homozygotes are at a greater risk of fatal encephalitis from WNV infection. It is remarkable that the CCR532 mutation was more frequent in the WNV-infected population than in the WNV-uninfected population, and CCR532 homozygotes exhibited a higher mortality from WNV infection [8
], indicating that CCR5 is a protective factor in WNV infection in humans as well as mice. Thus, the same chemokine receptor (CCR5) is an advantage or a disadvantage to the host, depending on the virus (WNV or HIV), although the reason for this phenomenon remains a mystery.
Genetic polymorphisms in Toll-like receptor (TLR) signaling components may also serve as risk factors for certain infectious diseases. Luke O’Neill (Dublin, Ireland) showed that a genetic polymorphism in an adaptor protein in the TLR signaling pathways, myeloid differentiation primary-response protein 88 (MyD88)-like adapter [MAL; also known as Toll/IL-1R (TIR) domain-containing adaptor protein (TIRAP)], is associated with susceptibility to severe malaria induced by Plasmodium falciparum. TLR activation is essential for provoking the innate response against invading pathogens, and TIRAPs, such as MyD88, MAL/TIRAP, TIR domain-containing adaptor-inducing IFN-ß (TRIF), and TRIF-related adaptor molecule, are involved in initiating TLR-mediated intracellular signaling. O’Neill showed that the substitution of serine for leucine at amino acid residue 180 of MAL prevents the variant (MAL L180) from interacting with TLR2 and thus makes it inactive in TLR2 signaling. It is interesting that wild-type MAL S180 homozygotes in mouse tend to follow a severe disease course in P. falciparum-induced malaria; heterozygotes (S180/L180) show a less severe course, and MAL L180 homozygotes show the least severe disease course. Thus, MAL L180 homozygosity appears to render individuals resistant to P. falciparum infections. Although the exact mechanism of this phenomenon remains unclear, excessive TLR2 signaling may be detrimental to the body’s effective defense against certain pathogens.
Amanda Proudfoot (Geneva, Switzerland) discussed the possibility of targeting the chemokine system for therapeutic purposes. In particular, she discussed the rationale behind interfering with the chemokine system and introduced several potential means of therapeutic intervention. These included modified chemokines such as Met-RANTES and amino-oxypentane-RANTES, which function as receptor antagonists, ligand-neutralizing antibodies, receptor-blocking antibodies, and small molecule receptor antagonists [9 ]. She also addressed exploiting the chemokine-glycosaminoglycan (GAG) interaction for therapeutic advantage. As the interaction with GAGs is thought to provide a mechanism for locally trapping chemokines at their site of production, this interaction could be an effective point of therapeutic intervention. Supporting this hypothesis, CCL5/RANTES, with a mutation in its GAG-binding site, shows little chemotactic activity in vivo, and administration of a large dose of the modified chemokine successfully reduces the clinical scores in experimental allergic encephalitis by inhibiting the recruitment of inflammatory cells.
M. Miyasaka pointed out that GAGs are not the only chemokine-binding molecules in vivo. He demonstrated that extracellular matrix (ECM) components such as fibronectin, collagen, laminin, and mac25/anigomodulin, which are expressed on high endothelial venules, can bind certain chemokines preferentially and that chemokines bound to these proteins efficiently provide directional cues to lymphocytes expressing cognate receptors. He proposed that matrix-bound chemokines may function with or without forming a concentration gradient [10 ]. In the presence of such a gradient, cells may respond by haptotaxis, i.e., migration across a gradient of molecules that are bound to the ECM. Conversely, in the absence of such a gradient, as long as the matrix-presented chemokines are located close enough to each other in multiple rings, cells can still respond by chemokinesis, i.e., a chemoattractant-induced, increased mobility of cells with random, nondirected movement. Receptor desensitization would inhibit the cells from responding to the chemokines that stimulated them previously, thereby preventing the cells from returning to their original location and helping them move directionally, for example, from the inside to the outside of inflamed blood vessels.
There were also several interesting talks about antigen-presenting cells (APCs). The precise discrimination between harmless antigens and dangerous pathogens by intestinal APCs is likely to be a key mechanism for the maintenance of gut immune homeostasis. The intestinal lamina propria (LP) contains a unique dendritic cell (DC) subset (LP-DC), which can constitutively endocytose apoptotic intestinal epithelial cells (IECs) and transport them to the T cell areas of mesenteric lymph nodes (MLNs). M. H. Jang reported one such unique LP-DC subset (CD11chiCD8intCD11bloLloß7hi), which migrates to the MLNs in a CCR7-dependent manner [11
]. The LP-DCs can present IEC-associated antigens to CD4+ T cells, inducing IL-4 and IL-10 expression, which indicates that LP-DCs may cross-present IEC-derived antigens to T cells in MLNs, favoring a Th2-prone environment in these nodes.
Hiroshi Kiyono (Tokyo, Japan) showed that eosinophils in the intestinal LP, which are Gr-1+CD11c+F4/80+CD11b+B220–, play an important role in the induction of tolerance to oral antigens via a transforming growth factor-ß-dependent but CD25+ T regulatory cell-independent mechanism. LP eosinophils may be able to negatively present antigen. So-Youn Woo (Seoul, Korea) showed that intestinal LP eosinophils exhibit chemotactic responses to CCL11/eotaxin and CCL25/thymus-expressed chemokine (TECK), which are produced by the intestinal epithelium. Neutralization of CCL25 and CCL11 inhibits the steady-state recruitment of eosinophils to the intestinal LP, indicating that these chemokines are involved in the trafficking of eosinophils into the intestinal LP.
Giorgio Trinchieri (Bethesda, MD) discussed interesting interactions between myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) [12 ]. He showed that an autocrine loop of type I IFN is required for IL-12p70 secretion by mDCs and that a paracrine loop of type I IFN from pDCs may amplify the IL-12 production by mDCs.
In summary, the International Cytokine Society Conference 2005 provided an excellent forum for discussing cutting-edge data about cytokines, chemokines, TLRs, cross-talk among these molecules, and novel immune cell subsets. Research on cytokines, chemokines, and their receptors will continue to be an area of rapid progress and high therapeutic promise in the next decade.
Received November 17, 2005; accepted March 6, 2006.
REFERENCES
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
