ABSTRACT
Precise intrathymic cell migration is important for thymocyte maturation and organ architecture. The orchestration of thymocyte trafficking, however, is not well understood at a molecular level. Here, we described highly regulated plexinD1 expression on CD4+CD8+ double positive (DP) thymocytes. PlexinD1 expression was further affected by the engagement of T cell receptor complex. Activation of plexinD1 via the ligand, semaphorin 3E, repressed CCL25 chemokine signaling via its receptor CCR9 in CD69+ thymocytes. In the absence of plexinD1, CD69+ thymocytes remained in the cortex, maturing to form ectopic single positive (SP) thymocyte clusters in Plxnd1-deficient fetal liver cell-transplanted mice. As a consequence, the boundary between DP and SP thymocytes at corticomedullary junctions was disrupted and medullary structures formed under the thymic capsule. These results demonstrate the importance of plexinD1 in directing migration of maturing thymocytes via modulation of biological responses to chemokine gradients.
Subject(s)
Cell Movement/immunology , Glycoproteins/metabolism , Membrane Glycoproteins/metabolism , Membrane Proteins/metabolism , Nerve Tissue Proteins/metabolism , T-Lymphocyte Subsets/immunology , Thymus Gland/immunology , Animals , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/immunology , Cell Movement/genetics , Cytoskeletal Proteins , Gene Expression Profiling , Glycoproteins/genetics , Intracellular Signaling Peptides and Proteins , Lectins, C-Type , Membrane Glycoproteins/genetics , Membrane Proteins/genetics , Mice , Mice, Knockout , Nerve Tissue Proteins/genetics , Receptors, CCR/metabolism , Semaphorins , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/metabolism , Thymus Gland/cytology , Thymus Gland/metabolismABSTRACT
Pancreatic adenocarcinoma is one of the most aggressive malignant tumors and represents the fourth leading cause of cancer-related death. The median survival of locally advanced pancreatic carcinoma is ten to thirteen months. In this year's American Society of Clinical Oncology (ASCO) Annual Meeting, several studies were presented with novel approaches towards treating locally advanced pancreatic cancer. Wild et al. (Abstract #4055) explored a novel tool of selective delivery of TNF-alpha intratumoral injection. This approach limited the systemic toxicity, and suggested survival benefit in only the subgroup of patients with locally advanced pancreatic adenocarcinoma with stage T1-T3. Two studies were presented which were designed to assess the use of two novel agents, targeting signaling pathways, in addition to gemcitabine. Van Laethem et al. (Abstract #4050) are testing the MEK inhibitor, BAY 86-9766 in combination with gemcitabine. However, treatment related toxicity is still of concern. In the other study, Evans et al. (Abstract #TPS4134) are testing the combination of dasatinib and gemcitabine. This is a placebo-controlled, randomized, double blind phase II study. However, results are not available. Stereotactic body radiotherapy (SBRT) is an emerging technology with the comparative efficacy of single fraction radiotherapy (as is used in radiosurgery) vs. fractionated SBRT still unknown. Herman et al. (Abstract #4045) examined the role of fractionated SBRT in locally advanced pancreatic cancer. The phase II results showed a median overall survival of 15.9 months, suggesting that SBRT may be an emerging tool in the multi-modality treatment of locally advanced pancreatic cancer.