Dances with leukocytes: how tetraspanin-enriched microdomains assemble to form endothelial adhesive platforms

Rather than just providing an unstructured adhesive surface for leukocytes, cytokine-activated endothelial cells assemble preexisting tetraspanin-enriched microdomains to form endothelial adhesive platforms (EAPs) and endothelial docking structures. In this issue of the Journal of Cell Biology, Barreiro et al. (Barreiro, O., M. Zamai, M. Yáñez-Mó, E. Tejera, P. López-Romero, P.N. Monk, E. Gratton, V.R. Caiolfa, and F. Sánchez-Madrid. 2008. J. Cell Biol. 183:527–542) show how the immunoglobulin superfamily adhesion molecules intercellular adhesion molecule (ICAM)–1 and vascular cell adhesion molecule (VCAM)–1 form nanoclusters with the tetraspanins CD9 and CD151 in a physiologically relevant system. Furthermore, convincing biochemical data suggest that these structures are distinct from lipid rafts

IL-17A-producing neutrophil-regulatory Tn lymphocytes

The proinflammatory cytokine IL-17A, mainly produced by specialized T cells, plays an important homeostatic role in regulating neutrophil production and blood neutrophil counts. This review will assemble and discuss the evidence for this function of IL-17A-producing cells, which are collectively called neutrophil-regulatory T cells or Tn cells. IL-17A-producing lymphocytes are most abundant in the mesenteric lymph node, where they account for 0.15% of all lymphocytes. About 60% of the Tn cells are γδ T cells, about 25% NKT-like cells, and less than 15% are CD4 T cells. These latter cells are also known as T-17 or ThIL-17 cells, a subset of Tn cells that also plays an important role in autoimmune diseases. IL-17A produced by Tn cells regulates the production of G-CSF, which in turn promotes the proliferation of promyelocytes and maturation of neutrophils. This homeostatic mechanism plays an important role in normal physiology and in host defense against bacterial infections. This review is aimed at highlighting the important role of IL-17A-producing T cells at the interface between the adaptive and innate immune syste

HGF Guides T Cells into the Heart

Expression of distinct homing receptors guides adaptive immune cells to antigen-rich tissue. In this issue of Immunity, Komarowska et al. (2015) describe an autocrine loop that is initiated by cardiac-expressed hepatocyte growth factor to direct T cells into the heart during inflammation and cardiac transplant rejection

ATVB Distinguished Scientist Award How Costimulatory and Coinhibitory Pathways Shape Atherosclerosis

Objective-Immune cells play a critical role in atherosclerosis. Costimulatory and coinhibitory molecules of the tumor necrosis factor receptor and CD28 immunoglobulin superfamilies not only shape T-cell and B-cell responses but also have a major effect on antigen-presenting cells and nonimmune cells. Approach and Results-Pharmacological inhibition or activation of costimulatory and coinhibitory molecules and genetic deletion demonstrated their involvement in atherosclerosis. This review highlights recent advances in understanding how costimulatory and coinhibitory pathways shape the immune response in atherosclerosis. Conclusions-Insights gained from costimulatory and coinhibitory molecule function in atherosclerosis may inform future therapeutic approaches

Transmission of integrin β7 transmembrane domain topology enables gut lymphoid tissue development.

Integrin activation regulates adhesion, extracellular matrix assembly, and cell migration, thereby playing an indispensable role in development and in many pathological processes. A proline mutation in the central integrin β3 transmembrane domain (TMD) creates a flexible kink that uncouples the topology of the inner half of the TMD from the outer half. In this study, using leukocyte integrin α4β7, which enables development of gut-associated lymphoid tissue (GALT), we examined the biological effect of such a proline mutation and report that it impairs agonist-induced talin-mediated activation of integrin α4β7, thereby inhibiting rolling lymphocyte arrest, a key step in transmigration. Furthermore, the α4β7(L721P) mutation blocks lymphocyte homing to and development of the GALT. These studies show that impairing the ability of an integrin β TMD to transmit talin-induced TMD topology inhibits agonist-induced physiological integrin activation and biological function in development

Mycophenolic acid suppresses granulopoiesis by inhibition of interleukin-17 production

Mycophenolic acid is a commonly used immunosuppressant after organ transplantation and in autoimmune diseases; however, myelosuppression is a major complication despite its largely favorable side-effect profile. Mycophenolic acid targets inosine monophosphate dehydrogenase, which is essential for T-cell proliferation. The T-cell cytokine interleukin-17 (IL-17 or IL-17A) and its receptor maintain normal neutrophilic granulocyte numbers in mice by induction of granulocyte-colony-stimulating factor. To test whether mycophenolic acid induces neutropenia by inhibiting IL-17-producing T cells, we treated C57Bl/6 mice with mycophenolate-mofetil (the orally available pro-drug) and found a dose-dependent decrease in blood neutrophils. This myelosuppressive effect was completely abolished in mice that lack the IL-17 receptor. Mycophenolic acid delayed myeloid recovery after bone marrow transplantation and decreased the percentage of IL-17-producing T cells in the spleen and thymus, and inhibited IL-17 production in human and mouse T cells in vitro. Injection of IL-17 during mycophenolic acid treatment overcame the suppression of the circulating neutrophil levels. Our study shows that mycophenolic acid suppresses neutrophil production by inhibiting IL-17 expression, suggesting that measurement of this interleukin might be useful in estimating the risk of neutropenia in clinical settings

Dynamics of in silico leukocyte rolling, activation, and adhesion

BACKGROUND: We present a multilevel, agent based, in silico model that represents the dynamics of rolling, activation, and adhesion of individual leukocytes in vitro. Object-oriented software components were designed, verified, plugged together, and then operated in ways that represent the molecular and cellular mechanisms believed responsible for leukocyte rolling and adhesion. The result is an in silico analogue of an experimental in vitro system. The experimentally measured, phenotypic attributes of the analogue were compared and contrasted to those of leukocytes in vitro from three different experimental conditions. RESULTS: The individual in silico dynamics of "rolling" on simulated P-selectin, and separately on simulated VCAM-1, were an acceptable match to individual in vitro distance-time and velocity-time measurements. The analogues are also able to represent the transition from rolling to adhesion on P-selectin and VCAM-1 in the presence of GRO-α chemokine. The individual in silico and in vitro behavioral similarities translated successfully to population level measures. These behavioral similarities were enabled in part by subdividing the functionality of the analogue's surface into 600 independent, "cell"-controlled, equally capable modules of comparable functionality. CONCLUSION: The overlap in phenotypic attributes of our analogue with those of leukocytes in vitro confirm the considerable potential of our model for studying the key events that determine the behavioral outcome of individual leukocytes during rolling, activation, and adhesion. Our results provide an important foundation and framework for future in silico research into plausible causal links between well-documented, subcellular molecular level events and the variety of systemic phenotypic attributes that distinguish normal leukocyte adhesion from abnormal disease-associated adhesion

Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages

Macrophages are found in tissues, body cavities, and mucosal surfaces. Most tissue macrophages are seeded in the early embryo before definitive hematopoiesis is established. Others are derived from blood monocytes. The macrophage lineage diversification and plasticity are key aspects of their functionality. Macrophages can also be generated from monocytes in vitro and undergo classical (LPS+IFN-γ) or alternative (IL-4) activation. In vivo, macrophages with different polarization and different activation markers coexist in tissues. Certain mouse strains preferentially promote T-helper-1 (Th1) responses and others Th2 responses. Their macrophages preferentially induce iNOS or arginase and have been called M1 and M2, respectively. In many publications, M1 and classically activated and M2 and alternatively activated are used interchangeably. We tested whether this is justified by comparing the gene lists positively [M1(=LPS+)] or negatively [M2(=LPS–)] correlated with the ratio of IL-12 and arginase 1 in transcriptomes of LPS-treated peritoneal macrophages with in vitro classically (LPS, IFN-γ) vs. alternatively activated (IL-4) bone marrow derived macrophages, both from published datasets. Although there is some overlap between in vivo M1(=LPS+) and in vitro classically activated (LPS+IFN-γ) and in vivo M2(=LPS–) and in vitro alternatively activated macrophages, many more genes are regulated in opposite or unrelated ways. Thus, M1(=LPS+) macrophages are not equivalent to classically activated, and M2(=LPS–) macrophages are not equivalent to alternatively activated macrophages. This fundamental discrepancy explains why most surface markers identified on in vitro generated macrophages do not translate to the in vivo situation. Valid in vivo M1/M2 surface markers remain to be discovered