BSP :: Current Immunology Reviews Home Page

Contents

Exosomes: Specific Intercellular Nano-Shuttles? Pp. 1-6
Ana Maria Barral & Matthias G. von Herrath
[Abstract] [Full text article]

Lipid-Based Membrane Microdomains in T Cell Activation Pp. 7-12
Paola Pizzo & Antonella Viola
[Abstract] [Full text article]

Activation and Costimulation of Intestinal T Cells: Independent and Collaborative Involvement of CD43, OX40, and Ly-6C Pp. 13-20
Dina Montufar-Solis & John R. Klein
[Abstract] [Full text article]

Peripheral Tolerization of Effector and Memory T Cells: Implications for Autoimmunity and Tumor-Immunity Pp. 21-28
Adam J. Adler
[Abstract] [Full text article]

Innate Immunity in the Skin: How Keratinocytes Fight Against Pathogens Pp. 29-42
Andor Pivarcsi, Istvan Nagy & Lajos Kemeny
[Abstract] [Full text article]

Combating Bacterial Pathogens Through Host Defense Gene Programs Pp. 43-54
Ryan M. O’Connell, Supriya K. Saha & Genhong Cheng
[Abstract] [Full text article]

The Double Identity of WSX-1 (IL-27R) as an Initiator and an Attenuator of Immune Responses Pp. 55-60
Hiroki Yoshida, Shinjiro Hamano & Yoshiyuki Miyazaki
[Abstract] [Full text article]

Mitochondrial Signal Transduction Abnormalities in Systemic Lupus Erythematosus Pp. 61-67
Gyorgy Nagy, Agnes Koncz, Paul Phillips & Andras Perl
[Abstract] [Full text article]

Accessibility Control of Recombination at Immunoglobulin Locus Pp. 69-79
Manabu Sugai, Hiroyuki Gonda, Yukiko Nambu, Yoshifumi Yokota & Akira Shimizu
[Abstract] [Full text article]

Toll-Like Receptor Signaling: Emerging Opportunities in Human Diseases and Medicine Pp. 81-90
Rabindra N. Bhattacharjee & Shizuo Akira
[Abstract] [Full text article]

Abstracts

[Back to top]
Exosomes: Specific Intercellular Nano-Shuttles?
Ana Maria Barral & Matthias G. von Herrath

[Full text article]

The term “exosome” was coined in 1981 (Trams et al, Biochim Biophys Acta, 1981, 645:63) when the presence of “exfoliated membrane vesicles with 5’-nucleotidase activity” was first reported. Since then, in the biomedical literature the term exosome has evolved to designate both the above mentioned small vesicles of endocytic origin and the 3’->5’ exonuclease complex involved in RNA processing and degradation. In the present review we will focus on the original definition of exosomes and particularly on their emerging role as intercellular signaling devices.

Exosomes are secreted by a variety of cells, particularly antigen-presenting cells such as DCs, B cells and macrophages. Enriched in MHC class I and II antigens and costimulatory molecules, they are considered to be an alternative pathway of antigen delivery and presentation. The use of exosomes engineered to prime the immune system against tumor antigens is a promising new arm of cancer immunotherapy. On the other hand, exosomes released by the tumor itself may provoke a tolerogenic response. Participation of exosomes in other immune mechanisms, such as platelet activation, mast cell degranulation, germinal center reaction and engulfment of apoptotic cells has also been postulated.

An evolutionary link between retroviruses and exosomes has recently been proposed. In general, viruses can use the host’s intracellular machinery for their budding, and exosomes may constitute a vehicle for transmission of pathogens and interaction with the immune system. A deeper knowledge of the cells targeted by exosomes and the mechanisms governing these interactions will give a clear picture of the role of exosomes as intercellular messengers.

[Back to top]
Lipid-Based Membrane Microdomains in T Cell Activation
Paola Pizzo & Antonella Viola

[Full text article]

The immune system is able to mount an immune response against antigens present in the body at very low concentrations and, at the same time, to discriminate precisely between an infectious stimulus and a non-infectious one. During T cell activation, this sensitivity and specificity are achieved by mechanisms of sustained interactions with antigen-presenting cells (APC) as well as by tunable activation thresholds and signal modulation. Thus, in addition to the interaction between the T cell receptor (TCR) and its ligand, T cell activation depends on the combination of many other events involving costimulatory and inhibitory receptors, actin cytoskeleton and lipid membrane microdomains. Lipid rafts, shingolipid- and cholesterol-rich membrane microdomains, seem to be primarily involved in initiation and propagation of the signal transduction cascade associated to lymphocyte activation and might be used by T cells to fine-tune their immune responsiveness. In this article, we discuss recent results indicating that rafts are responsible for the spatial and temporal organization of the T cell signal transduction.

[Back to top]
Activation and Costimulation of Intestinal T Cells: Independent and Collaborative Involvement of CD43, OX40, and Ly-6C
Dina Montufar-Solis & John R. Klein

[Full text article]

T cells are present in large numbers in the epithelial lining of the small and large intestine of humans and mice. Those cells, referred to as intraepithelial lymphocytes (IELs), are critical for maintaining an effective mucosal immune response against the onslaught of enteric infectious agents and intestinal neoplasia. However, because intestinal immunity must by necessity occur rapidly and efficiently, it is concomitantly important that the local intestinal immune response be curtailed so as not to result in conditions that lead to a destructive inflammatory environment as occurs in inflammatory bowel disease (IBD). Although many aspects of the IEL activation process remain to be understood, emerging evidence indicates that costimulatory molecules on IELs are critical for activation and that they hold the key to regulating intestinal immunity across many levels. In this article, the involvement of three IEL costimulatory molecules (CD43, OX40, and Ly-6C) — working independently or in collaboration—will be discussed in the context of immunity and disease in the human and mouse intestine, and the involvement of those in sustaining the IELs in a uniquely precarious but effective state of activation readiness will be explored.

[Back to top]
Peripheral Tolerization of Effector and Memory T Cells: Implications for Autoimmunity and Tumor-Immunity
Adam J. Adler

[Full text article]

Due to the random generation of T cell antigen receptors, a large fraction of developing T cells have the potential to recognize self-determinants. To prevent this self-reactive T cell repertoire from mediating autoimmunity, the immune system utilizes several mechanisms to induce tolerance to self. The majority of self-reactive T cells undergo negative selection (i.e., apoptosis) during development if their antigen receptors have high affinity for MHC-self-peptide complexes present in the thymus. Nonetheless, some T cells recognize self-epitopes that are not present in the thymus, and will thus reach maturation and migrate to peripheral lymphoid organs were they can be subject to a number of peripheral tolerance mechanisms such as deletion, inactivation (i.e., anergy) or suppression. While peripheral tolerization of naive (i.e., antigen-inexperienced) T cells has been studied extensively, there are potential situations in which self-reactive T cells might first encounter immunogenic forms of antigen (deriving from pathogens or vaccines) and thus be programmed to develop effector and memory functions. This article will review recent studies that have explored the potential of effector and memory T cells to undergo peripheral tolerization, as well as potential implications of these findings for autoimmunity and tumor-immunity.

[Back to top]
Innate Immunity in the Skin: How Keratinocytes Fight Against Pathogens
Andor Pivarcsi, Istvan Nagy & Lajos Kemeny

[Full text article]

The human skin is constantly exposed to a large number of external pathogens, due to the daily contact with the environment. The observation that extensive skin infections are relatively rare suggests the presence of an efficient host defense system at the skin surface. While the physical barrier function of the epidermis was formerly believed to play the major role in the protection against infections, the recent description of Toll-like receptors (TLRs) and antimicrobial peptides in the epidermis indicates that keratinocytes play an active role in innate immunity. To date TLR1, TLR2, TLR3, TLR4, TLR5, TLR6 and TLR9 have been described to be expressed in a constitutive or inducible manner in keratinocytes and to mediate the recognition of pathogen-associated molecular patterns (PAMPs). Recognition of PAMPs results in the production of proinflammatory mediators such as cytokines, chemokines and antimicrobial peptides in keratinocytes. Recent findings indicate the importance of these peptides as effector molecules of innate immunity, but also as regulators of acquired immune responses, inflammation and wound repair. This review considers the current findings regarding TLR expression in the epidermis and the role these receptors might serve in host defense. Finally, the clinical relevance of the functions of keratinocytes in the innate immunity will be discussed in this review.

[Back to top]
Combating Bacterial Pathogens Through Host Defense Gene Programs
Ryan M. O’Connell, Supriya K. Saha, & Genhong Cheng

[Full text article]

Antibiotic resistance, bioterrorism and microbial induced autoimmune disorders have made bacterial infections a growing concern in our society. To confront these challenges, numerous studies over the past decade have focused on improving our understanding of the early immune response against microbial pathogens. Results from these investigations have demonstrated that the mammalian host recognizes infectious organisms through pattern recognition receptors (PRRs) that subsequently activate signal transduction pathways leading to gene transactivation. Global gene expression analyses have revealed that PRRs induce a large number of different immunomodulatory genes that can be divided into gene programs; sets of genes involved in initiating specific immunological functions. This review will focus on the Toll-like receptor (TLR) family of PRRs with respect to microbial recognition, signaling specificity and regulation of selected gene programs. Furthermore, the ability of bacterially expressed virulence factors to interfere with TLR-mediated responses will be addressed.

[Back to top]
The Double Identity of WSX-1 (IL-27R) as an Initiator and an Attenuator of Immune Responses
Hiroki Yoshida, Shinjiro Hamano & Yoshiyuki Miyazaki

[Full text article]

Two heterodimeric cytokines, IL-23 and IL-27, were recently identified, which have structural and functional homology to IL-12. IL-27, composed of p28 plus Epstein Barr Virus-induced gene (EBI)-3, is a member of the IL-12 cytokine family. IL-27 is produced early after activation of antigen-presenting cells and induces proliferation of naïve CD4⁺ T cells upon antigen recognition. Stimulation of naïve CD4⁺ T cells with IL-27 through WSX-1, a subunit of functional IL-27 receptor complex, initiates the differentiation of CD4⁺ T cells into Th1 populations through induction of T-bet followed by expression of IL-12Rβ2. IL-27/WSX-1 thus is critical for proper induction of Th1 responses and lack of WSX-1 results in the impaired Th1 responses in mice. Recent studies revealed that L-27/WSX-1 signaling also has an anti-inflammatory property. In some protozoan infection, various pro-inflammatory cytokines including TNF-α and IL-6, and even IFN-γ, were over produced, causing lethal inflammatory responses in WSX-1^-/- mice. These data revealed that IL-27/WSX-1 has a suppressive role for pro-inflammatory cytokine production and that IL-27/WSX-1 may work to suppress and/or terminate immune responses and inflammation. Taken together, IL-27/WSX-1 thus has double identity as an initiator and as an attenuator of immune responses and inflammation.

[Back to top]
Mitochondrial Signal Transduction Abnormalities in Systemic Lupus Erythematosus
Gyorgy Nagy, Agnes Koncz, Paul Phillips & Andras Perl

[Full text article]

Engagement of T cell receptors by antigen-presenting cells or stimulation by cytokines determine whether the cell will become activated, anergic or die via apoptosis or necrosis. Ca²⁺ is a key second messenger that delivers signal from the cell surface, reactive oxygen intermediates (ROI) and nitric oxide (NO) are recently recognized as important mediators of T-cell activation. NO as a multifunctional intracellular and intercellular messenger induces mitochondrial biogenesis in many cell types such as lymphocytes. Mitochondria produce ROI and store and release Ca²⁺ in response to activation and death signals. Rapid Ca²⁺ fluxing is increased while sustained Ca²⁺ signaling is decreased in lupus T cells. Lupus T cells contain increased numbers and mass of mitochondria. Serum NO levels and production of NO by monocytes is increased in patients with systemic lupus erythematosus (SLE). Lupus T cells exhibit mitochondrial hyperpolarization and increased mitochondrial mass which confer predisposition to necrosis rather than apoptosis in response to repetitive activation and death signals. Exposure of normal T cells to NO dose-dependently increase the mitochondrial mass and mimic rapid and sustained Ca²⁺ signal abnormalities observed in lupus T cells. Thus, increased mitochondrial biogenesis may account for altered Ca²⁺ handling and represents novel targets for pharmacological intervention in SLE.

[Back to top]
Accessibility Control of Recombination at Immunoglobulin Locus
Manabu Sugai, Hiroyuki Gonda, Yukiko Nambu, Yoshifumi Yokota & Akira Shimizu

[Full text article]

During B cell development, two somatic DNA recombination events occur at the immunoglobulin heavy chain loci: VDJ recombination and class switch recombination (CSR). VDJ recombination assembles antigen receptor genes from a pool of gene segments. CSR exchanges the μ constant region of the immunoglobulin heavy chain gene for the other isotypes (γ1, γ2a, γ2b, γ3, α or ε). In both cases, the target specificity of recombination reactions seems to be regulated by structural changes of the target chromatin. In fact, many studies support this notion, called the “accessibility model”. In recent years, covalent modifications of histones have gained prominence as epigenetic markers that alter the properties of the associated DNA and contribute to structural changes of the target chromatin. This review focuses on the control of CSR by modulation of accessibility, and the role of histone modifications and germline transcription in CSR.

[Back to top]
Toll-Like Receptor Signaling: Emerging Opportunities in Human Diseases and Medicine
Rabindra N. Bhattacharjee & Shizuo Akira

[Full text article]

The family of Toll-like receptors (TLR1-TLR11) provides host defense in mammals by inducing pro-inflammatory innate immune response upon recognition of conserved structural component in pathogens. TLR mediated activation of signaling pathways that induce the expression of proinflammatory molecules is one of the well-studied but ever expanding fields of immunology. As a result, a wealth of information has been obtained which includes the identification of specific ligands of individual TLR, elucidation of their downstream signaling pathways, function of different adaptor proteins, activation of protein kinases and transcription factors that transcribe the genes for inflammatory molecules. TLRs not only sense microbial invasion but also can be activated by endogenous molecules as well as low molecular weight synthetic compounds. Given the role of innate immune machinery to provoke inflammation in host, TLRs signaling may be involved in many acute and chronic inflammatory processes in sterile and post-infection conditions such as, atherosclerosis, leprosy, inflammatory bowel syndrome (IBD), lung airway hyperactivity in allergic asthma, and in sepsis. By the same token, TLRs can also be associated with autoimmune diseases such as systemic lupus erythematosus (SLE) or other immune unresponsive diseases like cancer. In addition, synthetic organic compounds which enhance the function of TLRs can also be useful as potential adjutants to improve conventional vaccination strategy. Here we summarize the recent development on possible modulation of the TLR signaling pathway for therapeutic solution of multiple immune-related diseases.