Annual Review of Immunology - Volume 25, 2007

Integrins are cell adhesion molecules that mediate cell-cell, cell–extracellular matrix, and cell-pathogen interactions. They play critical roles for the immune system in leukocyte trafficking and migration, immunological synapse formation, costimulation, and phagocytosis. Integrin adhesiveness can be dynamically regulated through a process termed inside-out signaling. In addition, ligand binding transduces signals from the extracellular domain to the cytoplasm in the classical outside-in direction. Recent structural, biochemical, and biophysical studies have greatly advanced our understanding of the mechanisms of integrin bidirectional signaling across the plasma membrane. Large-scale reorientations of the ectodomain of up to 200 Å couple to conformational change in ligand-binding sites and are linked to changes in α and β subunit transmembrane domain association. In this review, we focus on integrin structure as it relates to affinity modulation, ligand binding, outside-in signaling, and cell surface distribution dynamics.

All hematopoietic cells, including T lymphocytes, originate from stem cells that reside in the bone marrow. Most hematopoietic lineages also mature in the bone marrow, but in this respect, T lymphocytes differ. Under normal circumstances, most T lymphocytes are produced in the thymus from marrow-derived progenitors that circulate in the blood. Cells that home to the thymus from the marrow possess the potential to generate multiple T and non-T lineages. However, there is little evidence to suggest that, once inside the thymus, they give rise to anything other than T cells. Thus, signals unique to the thymic microenvironment compel multipotent progenitors to commit to the T lineage, at the expense of other potential lineages. Summarizing what is known about the signals the thymus delivers to uncommitted progenitors, or to immature T-committed progenitors, to produce functional T cells is the focus of this review.

In light of recent data showing that both helper and cytotoxic T cells can detect even a single molecule of an agonist peptide-MHC, αβ T cells are clearly a type of sensory cell, comparable to any in the nervous system. In addition, endogenous (self) peptides bound to MHCs are not just important for thymic selection, but also play an integral role in T cell activation in the response to foreign antigens. With the multitude of specificities available to most T cells, they can thus be considered as a sensory organ, trained on self-peptide-MHCs and primed to detect nonself.

To combat infection, the fruit fly Drosophila melanogaster relies on multiple innate defense reactions, many of which are shared with higher organisms. These reactions include the use of physical barriers together with local and systemic immune responses. First, epithelia, such as those beneath the cuticle, in the alimentary tract, and in tracheae, act both as a physical barrier and local defense against pathogens by producing antimicrobial peptides and reactive oxygen species. Second, specialized hemocytes participate in phagocytosis and encapsulation of foreign intruders in the hemolymph. Finally, the fat body, a functional equivalent of the mammalian liver, produces humoral response molecules including antimicrobial peptides. Here we review our current knowledge of the molecular mechanisms underlying Drosophila defense reactions together with strategies evolved by pathogens to evade them.

Blood cells are constantly produced in the bone marrow (BM) of adult mammals. This constant turnover ultimately depends on a rare population of progenitors that displays self-renewal and multilineage differentiation potential, the hematopoietic stem cells (HSCs). It is generally accepted that HSCs are generated during embryonic development and sequentially colonize the fetal liver, the spleen, and finally the BM. Here we discuss the experimental evidence that argues for the extrinsic origin of HSCs and the potential locations where HSC generation might occur. The identification of the cellular components playing a role in the generation process, in these precise locations, will be important in understanding the molecular mechanisms involved in HSC production from undifferentiated mesoderm.

Chemokines are critical mediators of cell migration during routine immune surveillance, inflammation, and development. Chemokines bind to G protein–coupled receptors and cause conformational changes that trigger intracellular signaling pathways involved in cell movement and activation. Although chemokines evolved to benefit the host, inappropriate regulation or utilization of these proteins can contribute to or cause many diseases. Specific chemokine receptors provide the portals for HIV to get into cells, and others contribute to inflammatory diseases and cancer. Thus, there is significant interest in developing receptor antagonists. To this end, the structures of ligands coupled with mutagenesis studies have revealed mechanisms for antagonism based on modified proteins. Although little direct structural information is available on the receptors, binding of small molecules to mutant receptors has allowed the identification of key residues involved in the receptor-binding pockets. In this review, we discuss the current knowledge of chemokine:receptor structure and function, and its contribution to drug discovery.

Since its conception two decades ago, the Th1-Th2 paradigm has provided a framework for understanding T cell biology and the interplay of innate and adaptive immunity. Naive T cells differentiate into effector T cells with enhanced functional potential for orchestrating pathogen clearance largely under the guidance of cytokines produced by cells of the innate immune system that have been activated by recognition of those pathogens. This secondary education of post-thymic T cells provides a mechanism for appropriately matching adaptive immunity to frontline cues of the innate immune system. Owing in part to the rapid identification of novel cytokines of the IL-17 and IL-12 families using database searches, the factors that specify differentiation of a new effector T cell lineage—Th17—have now been identified, providing a new arm of adaptive immunity and presenting a unifying model that can explain many heretofore confusing aspects of immune regulation, immune pathogenesis, and host defense.