Current Immunology Reviews (Discontinued) - Volume 3, Issue 4, 2007

Extracellular matrix proteins play important roles in many different biological processes. Our recent work has discovered important roles for the ECM protein mindin in both innate and adaptive immune responses. Mindin is a member of the F-spondin family of extracellular matrix proteins, which are classified by the presence of an FS1/FS2 domain and one or more thrombospondin type 1 (TSR) repeats. Mindin is highly conserved throughout evolution and is broadly expressed in several organs including central and peripheral lymphoid tissues. As a component of the extracellular matrix, mindin exerts several important functions in immune responses. Mindin functions as a pattern recognition molecule for microbial pathogen recognition and is required for effective macrophage activation as well as phagocytosis of microbes. In addition, it promotes leukocyte trafficking during inflammation in vivo. Mindin is also essential for the adaptive immune response by inducing small GTPase expression in dendritic cells which is required for efficient T cell priming. These effects are largely mediated through the interaction of mindin with multiple cell surface integrins, which likely results in integrin clustering and the induction of downstream signaling cascades. The focus of this review is to highlight these recent discoveries that demonstrate the necessary roles for mindin during innate and adaptive immunity.

In the face of emerging infectious diseases, we are challenged to develop innovative vaccine strategies that can protect against rapidly evolving and highly virulent pathogens. Since CD4 T cells are needed to generate and maintain protective B cell and CD8 T cell immunity, new vaccines should ideally elicit both T and B cell memory. In order to generate long-lived immune memory in both T and B cell compartments, such vaccines will need to induce cross-reactive memory against highly conserved antigens within a given pathogen. Acute influenza infection provides a model system whereby the generation of T cell memory is influenced by residual antigen depots. These antigen depots persist for months after live virus clearance, and provide continued, low level T cell stimulation. Here we discuss the impact and implications of residual pathogen-derived antigen depots on the generation and maintenance of T cell immunity. We propose that effective vaccines may need to include persistent depots of conserved proteins to generate a functionally flexible memory T cell pool that can confer protection against rapidly evolving pathogens.

Lymph nodes (LNs) are crucial organs for triggering adaptive immune responses, and are localized at key places in the network of the lymphatic vascular system in order to filter tissue fluid exudates containing antigens effectively. Within the LN, immune cells are strategically compartmentalized to form a unique tissue architecture that is mechanically and functionally supported by several types of stromal cells of mesenchymal origin. In particular, one of the stromal cell types known as fibroblastic reticular cells (FRCs) produces extracellular matrix fibers and constructs an elaborate network of reticulum that serves as a foothold for immune cells' movement. This network of matrix fibers ensheathed by FRCs also functions as a transport system for low molecular weight materials, including lymph-borne soluble antigens. In addition, FRCs potentially control the localization and homeostasis of immune cells by producing various factors such as adhesion molecules, chemokines, and cytokines. Therefore, this type of less-understood stromal cell component in the LN plays a central role in the spatiotemporal regulation of adaptive immune surveillance.

During hematopoiesis, hematopoietic stem cells (HSCs) gradually lose their multi-potency and ultimately commit to a single lineage at certain period in the maturation process. Before entering the lineage commitment stage, progenitors have to go through multiple specification steps. During this progression, both external and internal cues may have effects on the cell fates of progenitors. However, it is not clear how extrinsic signals such as cytokines or growth factors from the microenvironment and intrinsic cell differentiation programs are coordinated and determined for lineage specification and commitment during hematopoiesis. Nevertheless, it has been assumed that upon lineage commitment, progenitors follow a hierarchical and linear differentiation program. Recently, the issues of developmental plasticity or latent differentiation potential in lineage-committed progenitors have been documented, although lineage commitment has been thought to be an irreversible event. Therefore, we may need to revisit the issue of how “lineage commitment” is determined in the hematopoietic system at the molecular level. In this review, we would like to propose a revised model for lineage commitment and give an overview of recent advances in understanding how lineage decision is made.

The activation of intracellular signaling pathways by the engagement of ligands with cell-surface receptors is a key event in determining the fate and function of cells. While these outcomes are primarily determined by the nature of the ligand and its receptor, proteins that negatively regulate the strength and duration of these signals are also critical components in this process. In recent years the E3 ubiquitin ligases c-Cbl and Cbl-b have emerged as prominent negative regulators of signaling responses initiated from antigen receptors on thymocytes and T cells respectively. In this review we focus on the role of Cbl-b in regulating T cell signaling and function and update new and exciting findings relating to Cbl-b deficient T cells that promote the rejection of tumors.

Insect immune systems which lack the type of adaptive immunity known in vertebrates rely on several mechanisms including solid barriers against the environment, rapid coagulation of hemolymph after wounding, the formation of aggregates that immobilize and kill foreign invaders, phagocytosis, and the production of antimicrobial peptides. The mode of action and the regulation of the expression of antimicrobial peptides have been studied intensively for more than three decades and are now increasingly well understood. In addition, the characterization of several key molecules involved in other branches of insect immunity has led to a deeper and much more comprehensive understanding of innate immunity in insects. Here we focus on the current status of our view of immunity in the vinegar fly Drosophila melanogaster, the best characterized insect model. We also discuss how evolutionary and ecological forces may have shaped immune responses in Drosophila as compared to other insect species. Finally, several infection models reveal finely-tuned and pathogen-dependent interactions between Drosophila immunity and fly physiology.

Primary Sjogren's syndrome (pSS) is a systemic as well as an organ-specific autoimmune disease characterized by lymphocytic infiltration of the glandular epithelial tissue. It has been reported that pSS patients have a relatively increased risk for the development of lymphoma and various factors such as cytokine stimulation, environmental exposures and viral infections as well as genetic events may contribute to the development of lymphoma in pSS patients. Over the past few decades, numerous efforts have been undertaken to search for the relationship between lymphoma and pSS, for example advances in molecular biology for clonality analysis and well-linked register cohort studies for the predictive value of clinical, laboratory and histological findings. Despite this, mechanisms and prediction of lymphoma development in pSS patients still remain to be defined. In this review we have summarized the current knowledge concerning incidence and risk factors of lymphoma development in pSS patients. In addition, the most recent discoveries in the emergence and treatment of lymphoma in pSS patients and the possible mechanism of lymphoma development are also discussed.