Begell House Inc.
Critical Reviews™ in Immunology
CRI
1040-8401
26
6
2006
Regulation of Thymocyte Survival by Transcriptional Coactivators
475-486
10.1615/CritRevImmunol.v26.i6.10
Huimin
Xie
Department of Microbiology & Immunology, College of Medicine, University of Illinois, Chicago, IL
Zhaofeng
Huang
Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080 P.R. China
Ruiqing
Wang
Division of Immunology, Beckman Research Institute of the City of Hope; Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010
Zuoming
Sun
City of Hope
A majority of the developing T cells are eliminated by apoptosis because they do not meet the positive and negative selection criteria. Developing T cells are thus susceptible to apoptotic signals. On the other hand, there are mechanisms to prevent developing T cells from premature apoptosis. Maintenance of a fine balance between life and death is thus critical for successful completion of T-cell development. Our recent studies demonstrated an essential role of transcriptional coactivators in maintaining such a balance for developing T cells. Transcriptional coactivators are recruited by transcriptional factors to quantitatively regulate gene expression via modifying chromatin structure. Two transcriptional factors, TCF-1 and RORγt, are required to upregulate the levels of Bcl-xL, a critical survival factor for CD4+CD8+ double-positive thymocytes. However, TCF-1 and RORγt by themselves are not sufficient to stimulate Bcl-xL expression. Transcriptional coactivator β-catenin recruited by TCF-1, and steroid receptor coactivators (SRCs) recruited by RORγt, are also required for optimal stimulation of Bcl-xL expression. Thus, transcriptional coactivators are a substantial component of the transcriptional machinery to regulate thymocye survival, ensuring the completion of T-cell development.
The Proteasome and Its Inhibitors in Immune Regulation and Immune Disorders
487-498
10.1615/CritRevImmunol.v26.i6.20
Alessio
Nencioni
Department of Internal Medicine, University of Genova, 16132 Genova, Italy; and Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Frank
Grunebach
Department of Hematology, Oncology and Immunology, University of Tübingen, D-72076 Tübingen, Germany
Franco
Patrone
Department of Internal Medicine, University of Genova, 16132 Genova, Italy
Alberto
Ballestrero
Department of Internal Medicine, University of Genova, 16132 Genova, Italy
Peter
Brossart
Department of Hematology, Oncology and Immunology, University of Tübingen, Otfried Muller Str. 10; D-72076 Tübingen, Germany
The ubiquitin-proteasome pathway is a well-characterized mechanism deputed to the degradation of intracellular proteins. Proteasomal degradation intervenes in the regulation of numerous cellular functions including signal transduction, apoptosis, cell cycle, and antigen presentation. In vitro and in vivo studies have shown that both normal and malignant cells of the immune system are exquisitely affected by inhibition of proteasome activity. This property is currently exploited in the treatment of multiple myeloma and mantle cell lymphoma, two B-cell malignancies that respond to treatment with the proteasome inhibitor bortezomib. Pharmacological inhibitors of the proteasome also affect function and survival of B and T lymphocytes and of dendritic cells and were shown to reduce autoimmune and inflammatory manifestations in several models of immune-mediated disorders. The present review offers an overview of the mechanisms implicated in the immunomodulatory effects of proteasome inhibitors and discusses prospective future applications for these small molecules in immune and inflammatory diseases.
Regulation of Immune Response by P2X7 Receptor
499-513
10.1615/CritRevImmunol.v26.i6.30
Lanfen
Chen
Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Ave. F-520, Bronx, NY 10461
Celia F.
Brosnan
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461
The P2X7 receptor is an ATP-gated cation channel that is widely expressed in cells of the immune system. Signal transduction is accompanied by fast influx of Ca2+ and Na+, and efflux of K+. This receptor differs from other members of the P2X family in its relatively low affinity for ATP, the presence of a long C-terminal region that contains several protein-protein interaction motifs, and the activation of two membrane conductance states following receptor ligation. In the immune system, this receptor has been implicated in the processing and release of cytokines such as IL-1β, and in the initiation of cell death via both apoptotic and necrotic pathways. As such, it has been proposed to function as a major regulator of inflammation. Consistent with this hypothesis, inactivation of this receptor in mice modulates disease pathogenesis in several animal models of inflammatory and autoimmune diseases. Loss-of-function polymorphisms have also been noted in the human population, and there is accumulating evidence that these polymorphisms are linked to certain diseases. In this article, we review the current status of research in this field, with particular emphasis on the signaling pathways activated by this receptor, the mechanisms involved in the initiation of cell death, and associations with disease states in mice and humans.
Immunological Protection Against Mycobacterium tuberculosis Infection
515-526
10.1615/CritRevImmunol.v26.i6.40
Yasunobu
Yoshikai
Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582
Mycobacterium tuberculosis (Mtb) invades the lung via an airborne pathway, and the bacteria reach the lung alveoli and are then engulfed by alveolar macrophages in innate immunity, which uses germline-encoded pattern recognition receptors such as the mannose receptor and Toll-like receptor for recognition of the pathogen. Mtb can survive in phagosomes of macrophages by escaping from lysosomal enzyme and reactive nitrogen intermediate toxicity. Dendritic cells transport Mtb from lung mucosa to draining lymph nodes and present the mycobacterial antigens to CD4+ and CD8+ T cells in adaptive immunity, which uses antigen-specific receptors formed by somatic gene rearrangement. Natural memory T cells such as γδ T cells and CD 1-restricted T cells are also stimulated and serve to shape the subsequent development of T-helper 1-dominant immunity, which induces granuloma at the initial focus of infection, is sufficient to prevent acute tuberculosis, but is unable to eradicate the infection completely. Once the host's defense becomes compromised, reactivation of the disease, which is called latent infection with Mtb, occurs. Recent progress in elucidating adaptive immune responses to acute and latent infection with Mtb may lead to the establishment of effective therapeutic and prophylactic approaches for controlling Mtb infection.
DNA Motifs Suppressing TLR9 Responses
527-544
10.1615/CritRevImmunol.v26.i6.50
Angela
Trieu
Institute for Molecular Bioscience and CRC for Chronic Inflammatory Diseases, University of Queensland, Brisbane 4072, Australia
Tara L.
Roberts
Institute for Molecular Bioscience and CRC for Chronic Inflammatory Diseases, University of Queensland, Brisbane 4072, Australia
Jasmyn A.
Dunn
Institute for Molecular Bioscience and CRC for Chronic Inflammatory Diseases, University of Queensland, Brisbane 4072, Australia.
Matthew J.
Sweet
The University of Queensland, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, Qld, 4072, Australia
Katryn J.
Stacey
Institute for Molecular Bioscience and CRC for Chronic Inflammatory Diseases, University of Queensland, Brisbane 4072, Australia
Immune cells respond to bacterial DNA containing unmethylated CpG motifs via Toll-like receptor 9 (TLR9). Given the apparent role of TLR9 in development of systemic lupus erythematosus (SLE), there is interest in the development of TLR9 inhibitors. TLR9-mediated responses are reported to be inhibited by a confusing variety of different DNA sequences and structures. To aid characterization, we have provisionally categorized TLR9-inhibitory oligodeoxynucleotides (ODN) into 4 classes, on the basis of sequence and probable mode of action. Class I are short G-rich ODN, which show sequence-specific inhibition of all TLR9 responses, and may be direct competitive inhibitors for DNA binding to TLR9. Class II are telomeric repeat motifs that inhibit STAT signaling, and thus are not specific to TLR9 responses. Because Class II ODN are generally made as 24-base phosphorothioate-modified ODN (PS-ODN), they also fall into Class IV, defined as long PS-ODN, which inhibit TLR9 responses in a sequence-nonspecific manner. Class III includes oligo (dG) that forms a 4-stranded structure and inhibits DNA uptake. The Class I G-rich motifs show the most promise as selective and potent TLR9 inhibitors for therapeutic applications.
Human Defensins and Cathelicidins in the Skin: Beyond Direct Antimicrobial Properties
545-576
10.1615/CritRevImmunol.v26.i6.60
Francois
Niyonsaba
Atopy (Allergy) Research Center, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Isao
Nagaoka
Department of Host Defense and Biochemical Research, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Hideoki
Ogawa
Atopy (Allergy) Research Center, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
A cutaneous barrier defends the body against invading pathogenic microorganisms due to both innate and adaptive immunity. The innate immune system comprises hundreds of peptides/proteins, which have potent microbicidal activities at low concentrations. Among these microbicidal agents, an increasing body of research has suggested that a vast arsenal of antimicrobial peptides composed of defensins and cathelicidins are key players in cutaneous immunity. Mainly produced by phagocytes and epithelial cells, defensins and cathelicidins directly or indirectly kill a wide range of bacteria, fungi, and viruses. However, it is increasingly evident that these peptides not only act as endogenous antibiotics but also display additional roles, such as regulation of inflammatory and immune responses, chemoattracting immune or inflammatory cells to wound or infection/inflammation sites, acceleration of angiogenesis, promotion of wound healing, and reepithelization, and binding and neutralizing of lipopolysaccharides. Here, we review the skin-derived antimicrobial peptides with an emphasis on their role in skin immune responses. We present an overview of defensin and cathelicidin structure and expression, clarify their various functions beyond microbicidal properties, and describe their modes of action. Moreover, we discuss the roles of these peptides in skin diseases and highlight their possible use in near therapeutic development.
Subject Index, Author Index
577-580
10.1615/CritRevImmunol.v26.i6.70