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Current Immunology Reviews (v.4, #4)

The Expanding Universe of γ δ T Lymphocytes: Subsets, Generation and Function by Serena Meraviglia, Nadia Caccamo, Carmela La Mendola, Giuliana Guggino, Francesco Dieli (pp. 183-189).
and#947;and#948; T cells which express the Vand#947;9 and Vand#948;2 gene products are unique to primates and represent only a minor population of peripheral blood T lymphocytes. They recognize nonpeptidic phosphoantigens in an MHC-unrestricted fashion and show low dependence on costimulation. The ability of Vand#947;9Vand#948;2 T cells to develop immunological memory remains debated. Vand#947;9Vand#948;2 T cells are able to mount both immediate effector functions and memory anamnestic responses upon microbial reinfection, suggestive of the existence of different functional subsets. However, how Vand#947;9Vand#948;2 T cells mediate the different facets of a memory response remains largely obscure. In this review we highlight recent findings that demonstrate that Vand#947;9Vand#948;2 cells are a very heterogeneous population of T lymphocytes and possess phenotypic and functional features very close to those of conventional and#945;and#946; T lymphocytes: they comprise distinct naive, memory and effector populations that can be distinguished on the basis of surface markers expression, migratory properties and effector functions.

Negative Regulation of TCR Signaling in Immunological Tolerance: Taming Good and Evil by Martina Gatzka, Craig Walsh (pp. 190-198).
To prevent the occurrence and expansion of autoreactive T cell clones, and hence the development of autoimmune disease (such as multiple sclerosis, rheumatoid arthritis, lupus erythematosus, and diabetes), the healthy immune system is equipped with a variety of immunological mechanisms, summarized as self-tolerance. The strength and frequency of the T cell receptor (TCR) signal as well as the costimulatory context critically control T cell fate and the composition of the T cell repertoire at different stages of lymphoid development. Central tolerance mechanisms in the thymus cause developing T cells with high affinity for self-peptide-MHC to undergo clonal deletion via programmed cell death (apoptosis) in a process referred to as negative selection. In contrast, T cells with a weak affinity are positively selected or, if the signal is just below the deletional threshold, enter a pathway to become regulatory T cells (Treg). Peripheral tolerance involves functional inactivation (and#x201C;anergyand#x201D;), suppression or extrathymic clonal deletion of autoreactive T cells that have escaped negative selection. The activation thresholds of TCR- and costimulatory-signaling pathways are modified by different groups of negative regulatory proteins with distinct developmentally regulated expression/activation patterns and functional mechanisms. This review provides an overview of the key negative regulators of T cell receptor signaling, including the Cbl family of ubiquitin ligases, phosphatases, the Dok family of adaptor proteins, as well as the serinethreonine kinase Drak2, and compares their differential impact on central and peripheral tolerance mechanisms, including clonal deletion, anergy and Treg suppression. Furthermore, the impact of targeting the related genes in mice on the susceptibility to different autoimmune diseases as well as the therapeutic potential of developing specific and effective immune treatments that modify these negative regulators of TCR signaling are explored.

From the Obscure and Mysterious Acute Phase Response to Toll-Like Receptors and the Cytokine Network by Aleksander Koj (pp. 199-214).
The discovery of C-reactive protein (CRP) almost 80 years ago in the blood of patients with various infectious and inflammatory diseases initiated studies on the mysterious biological phenomenon called and#x201C;the acute phase responseand#x201D; (APR). The complex metabolic alterations accompanying APR include changes in the plasma concentration of the majority of liver-produced proteins - acute phase proteins (APPs). The search for mediators released from the site of injury and able to stimulate hepatocytes led to the discovery of and#x201C;Leukocytic Endogenous Mediatorand#x201D; (or and#x201D;Endogenous Pyrogenand#x201D;), initially identified with interleukin-1. Only in 1987 was the main factor able to induce the majority of symptoms of APR discovered and named interleukin-6 (IL-6). The current paradigm assumes that APR is elicited by numerous proinflammatory cytokines, the principal role being played by the IL-6-family. The last decade has brought about significant progress in understanding the initiation of the acute phase response (recognition of pathogens by Toll-like receptors), interaction of cytokines and their receptors (origin and importance of soluble cytokine receptors, construction of hypercytokines by protein fusion), the mechanism of multi-step signal transduction from the plasma membrane to nuclear transcription factors (including the role of MAP kinases), as well as elucidation of the role of receptor cross-talk in cytokine networks in health and disease. Genomic techniques indicate that hundreds of genes participate in the development of APR. The data presented here emphasize the growing importance of APR for clinical medicine and confirm the close relationship between acute phase response and innate immunity.

Hepatocytes as Cytotoxic Effector Cells by Clifford Guy, Tomasz Michalak (pp. 215-220).
The liver is increasingly recognized as an immune competent organ wherein aberrant T cell responses to dietary or autoantigens are suppressed, thereby contributing to the maintenance of peripheral immune tolerance. Furthermore, the liver is constitutively capable of trapping and retention of activated T cells, irrespective of their antigenic specificity, leading to the proposed hypothesis that it may represent a site of elimination for activated lymphocytes. The structure of the liver readily facilitates the interaction of activated lymphocytes with other cells of the liver parenchyma, including hepatocytes. Since we have recently reported that hepatocytes constitutively express both CD95 ligand (CD95L or Fas ligand) and perforin cytotoxic molecules, which are biologically active and able to induce lysis of target cells, the cytolytic capacity of hepatocytes may contribute to the downregulation and contraction of T cell responses, as well as to elimination of other cells passing through or residing in the liver. Additionally, since we have found that these cytolytic pathways may be differentially regulated in hepatocytes in response to inflammatory cytokines, including interferon gamma (IFNand#947;) and tumor necrosis factor alpha (TNF), hepatocytes should be considered as cytotoxic effector cells which may modulate the development and outcome of inflammatory diseases affecting the liver.

Role of TARC/CCL17 and CTACK/CCL27 in the Pathogenesis of Atopic Dermatitis by Hidehisa Saeki, Kunihiko Tamaki (pp. 221-229).
TARC/CCL17 is designated as a Th2 type chemokine since it binds to CCR4. CTACK/CCL27 is a ligand for CCR10 and is selectively expressed in skin. Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by the predominant infiltration of Th2-type cells, especially in the acute phase. We have determined that serum levels of TARC and CTACK are elevated in AD patients and reflect the disease activity of AD. We investigated the regulation of production of TARC and CTACK from the human keratinocyte (KC) cell line, HaCaT cells. Production of both was upregulated after stimulation with inflammatory cytokines TNF-and#945;/IFN-and#947; and TNF-and#945;/IL-1and#946;, respectively, and the upregulated production was downregulated by adding inhibitors for nuclear factor kappa B (NFand#954;B) and p38. We have created transgenic (Tg) mice in which TARC or CTACK is overexpressed in KC. Interestingly, both TARC Tg mice and CTACK Tg mice show enhanced contact hypersensitivity to Th2, but not to Th1 stimuli. AD-like conditions such as increased number of mast cells and elevated levels of serum IgE were observed in both Tg mice by Th2-type stimuli. Thus, TARC and CTACK may participate in the pathogenesis of Th2-shifted skin diseases such as AD.

Role of Leptin in the Immune System by Patricia Fernandez-Riejos, Carmen Gonzalez-Yanes, Souad Najib, Consuelo Martin-Romero, Jose Santos-Alvarez, Victor Sanchez-Margalet (pp. 230-234).
Adipose tissue is no longer considered mere energy storage, but an important endocrine organ that produces many signals in a tightly regulated manner. Leptin is one of the most important hormones secreted by the adipocyte, with a variety of physiological roles related with the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. The adipocyte-derived hormone leptin has been shown to regulate the immune response both in normal as well as in pathological conditions. Leptin's modulation of the immune system is exerted at the development, proliferation, anti-apoptotic, maturation, and activation levels. The role of leptin in regulating immune response has been assessed in vitro as well as in clinical studies. Both the innate and adaptative immune responses are regulated by leptin. Every cell type involved in immunity can be modulated by leptin. In fact, leptin receptors have been found in neutrophils, monocytes, and lymphocytes, as well as belonging to the family of class I cytokine receptors. Moreover, leptin activates similar signaling pathways to those engaged by other members of the family. The overall leptin action in the immune system is a proinflammatory effect, activating proinflammatory cells, promoting T-helper 1 responses, and mediating the production of the other proinflammatory cytokines, such as tumor necrosis factor- and#945;, interleukin (IL)-2, or IL-6. Leptin receptor is also upregulated by proinflammatory signals. It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders such as autoimmune diseases are associated with increased secretion of leptin and production of proinflammatory pathogenic cytokines. Thus, leptin is a mediator of the inflammatory response, and could have also a permissive role in the development of autoimmune diseases.

Antigenic Peptide Vaccination: Provoking Immune Response and Clinical Benefit for Cancer by Tomohide Tsukahara, Toshihiko Torigoe, Yasuaki Tamura, Takuro Wada, Satoshi Kawaguchi, Tetsuhiro Tsuruma, Koichi Hirata, Toshihiko Yamashita, Noriyuki Sato (pp. 235-241).
Recent immunotherapy depends largely on understanding of the molecular interactions between T cell receptors (TCR) on cytotoxic T lymphocytes (CTL) and peptide/MHC class I complexes on tumor cells. Many tumor antigens identified by cDNA library expression cloning methods, especially from malignant melanoma, have greatly contributed to clarifying such mechanisms and led to peptide vaccination trials, mainly for patients with melanoma. Although the objective tumor regression rate mediated by peptide vaccination is still low compared to adoptive cell transfer therapy, antigenic peptide vaccination can cause a constant objective response generally evaluated as stable disease or decreased serum levels of tumor markers. In addition, recent trials in the adjuvant setting showed some suppressive effects against recurrence. Therefore, peptide vaccination still has potential for clinical benefits in patients with various cancers. For further improvement of peptide vaccination, we considered that (i) novel antigenic peptides, (ii) effective adjuvants, (iii) more sensitive immunological monitoring and (iv) drugs up-regulating HLA class I molecules might be important.

Immunological Aspects of Adult T-Cell Leukemia/Lymphoma (ATLL), a Possible Neoplasm of Regulatory T-Cells by Yasuaki Yamada, Shimeru Kamihira (pp. 242-250).
Adult T-cell leukemia/lymphoma (ATLL) is a distinct disease caused by the first discovered human oncogenic retrovirus, human T-cell leukemia virus type-1 (HTLV-1). The peculiarity of this disease is not only in its causative agent HTLV-1 but also in the character of leukemia cells. ATLL cells express the mature helper/inducer T-cell antigens, CD2, CD3, CD4 and CD5 but usually lacking CD8. Despite CD4 expression, it has long been known that ATLL cells exhibit strong immunosuppressive activity in vitro. Notably, ATLL patients are in severely immunosuppressed conditions and this causes higher incidences of opportunistic infections than other types of leukemia and lymphoma. Since ATLL cells constitutively express CD25, this prompted investigators to study ATLL cells from the viewpoint of regulatory T cells (Treg cells). ATLL cells satisfy all the criteria of Treg cells, as they express Foxp3, the master gene of Treg lineage, the glucocorticoid-induced TNF receptor (GITR), and the cytotoxic T-lymphocyte associated molecul-4 (CTLA-4). Moreover, other profiles including chemokine receptor expression also support that ATLL is a neoplasm of Treg cell origin. Here we review the immunological aspects of ATLL cells and discuss this cell origin.
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