Chemokines and the Tissue-Specific Migration of Lymphocytes

AbstractTissue-selective trafficking of memory and effector T and B lymphocytes is mediated by unique combinations of adhesion molecules and chemokines. The discovery of several related epithelial-expressed chemokines (TECK/CCL25 in small intestine, CTACK/CCL27 in skin, and MEC/CCL28 in diverse mucosal sites) now highlights an important role for epithelial cells in controlling homeostatic lymphocyte trafficking, including the localization of cutaneous and intestinal memory T cells, and of IgA plasma cells. Consitutively expressed epithelial chemokines may help determine the character of local immune responses and contribute to the systemic organization of the immune system

Key Role of Local Regulation in Chemosensing Revealed by a New Molecular Interaction-Based Modeling Method

The signaling network underlying eukaryotic chemosensing is a complex combination of receptor-mediated transmembrane signals, lipid modifications, protein translocations, and differential activation/deactivation of membrane-bound and cytosolic components. As such, it provides particularly interesting challenges for a combined computational and experimental analysis. We developed a novel detailed molecular signaling model that, when used to simulate the response to the attractant cyclic adenosine monophosphate (cAMP), made nontrivial predictions about Dictyostelium chemosensing. These predictions, including the unexpected existence of spatially asymmetrical, multiphasic, cyclic adenosine monophosphate–induced PTEN translocation and phosphatidylinositol-(3,4,5)P(3) generation, were experimentally verified by quantitative single-cell microscopy leading us to propose significant modifications to the current standard model for chemoattractant-induced biochemical polarization in this organism. Key to this successful modeling effort was the use of “Simmune,” a new software package that supports the facile development and testing of detailed computational representations of cellular behavior. An intuitive interface allows user definition of complex signaling networks based on the definition of specific molecular binding site interactions and the subcellular localization of molecules. It automatically translates such inputs into spatially resolved simulations and dynamic graphical representations of the resulting signaling network that can be explored in a manner that closely parallels wet lab experimental procedures. These features of Simmune were critical to the model development and analysis presented here and are likely to be useful in the computational investigation of many aspects of cell biology

Lymphocyte Cc Chemokine Receptor 9 and Epithelial Thymus-Expressed Chemokine (Teck) Expression Distinguish the Small Intestinal Immune Compartment: Epithelial Expression of Tissue-Specific Chemokines as an Organizing Principle in Regional Immunity

The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4+ and CD8+ T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9+, and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9−. TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses

Multiwavelength Monitoring of the BL Lacertae Object PKS 2155-304 in May 1994. I. The Ground-Based Campaign

Optical, near-infrared, and radio observations of the BL Lac object PKS2155-304 were obtained simultaneously with a continuous UV/EUV/X-ray monitoring campaign in 1994 May. Further optical observations were gathered throughout most of 1994. The radio, millimeter, and near-infrared data show no strong correlations with the higher energies. The optical light curves exhibit flickering of 0.2-0.3 mag on timescales of 1-2 days, superimposed on longer timescale variations. Rapid variations of ~0.01 mag/min, which, if real, are the fastest seen to date for any BL Lac object. Small (0.2-0.3 mag) increases in the V and R bands occur simultaneously with a flare seen at higher energies. All optical wavebands (UBVRI) track each other well over the period of observation with no detectable delay. For most of the period the average colors remain relatively constant, although there is a tendency for the colors (in particular B-V) to vary more when the source fades. In polarized light, PKS 2155-304 showed strong color dependence and the highest optical polarization (U = 14.3%) ever observed for this source. The polarization variations trace the flares seen in the ultraviolet flux.Comment: 45 pages, latex file with encapsulated postscript, accepted to the Astrophysical Journa

Incompatibilities Involving Yeast Mismatch Repair Genes: A Role for Genetic Modifiers and Implications for Disease Penetrance and Variation in Genomic Mutation Rates

Genetic background effects underlie the penetrance of most genetically determined phenotypes, including human diseases. To explore how such effects can modify a mutant phenotype in a genetically tractable system, we examined an incompatibility involving the MLH1 and PMS1 mismatch repair genes using a large population sample of geographically and ecologically diverse Saccharomyces cerevisiae strains. The mismatch repair incompatibility segregates into naturally occurring yeast strains, with no strain bearing the deleterious combination. In assays measuring the mutator phenotype conferred by different combinations of MLH1 and PMS1 from these strains, we observed a mutator phenotype only in combinations predicted to be incompatible. Surprisingly, intragenic modifiers could be mapped that specifically altered the strength of the incompatibility over a 20-fold range. Together, these observations provide a powerful model in which to understand the basis of disease penetrance and how such genetic variation, created through mating, could result in new mutations that could be the raw material of adaptive evolution in yeast populations