Cystatins, cysteine peptidase inhibitors, as regulators of immune cell cytotoxicity

Cystatins comprise a superfamily of evolutionarily related proteins, present in all living organisms, from protozoa to mammals. They act as inhibitors of cysteine peptidases although they can also function independently of their inhibitory function. Cysteine cathepsins are implicated in various physiological and pathological processes. In the immune response they are involved in antigen processing and presentation, the cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), migration and adhesion of immune cells, cytokine and growth factor regulation and toll-like receptor signalling. Cystatins are probably involved in the regulation of all these processes; importantly, cystatin F has a crucial role in the regulation of immune cell cytotoxicity. NK cells and CTLs exploit the granzyme/perforin pathway for target cell killing, with perforin and granzymes as crucial effector molecules. Granzymes are synthesized as inactive pro-granzymes and need to be proteolytically activated by cathepsins C and H. Cystatin F is the main regulator of the activity of cathepsins C and H in cytotoxic cells and, consequently, regulates their cytotoxicity. The role of cystatins and cysteine cathepsins in the immune response is presented, with emphasis on their role in the regulation of cytotoxicity of NK cells and CTLs.</p

Expression of the Immune Checkpoint Protein VISTA Is Differentially Regulated by the TGF-β1 - Smad3 Signaling Pathway in Rapidly Proliferating Human Cells and T Lymphocytes.

Immune checkpoint proteins play crucial roles in human embryonic development but are also used by cancer cells to escape immune surveillance. These proteins and biochemical pathways associated with them form a complex machinery capable of blocking the ability of cytotoxic immune lymphoid cells to attack cancer cells and, ultimately, to fully suppress anti-tumor immunity. One of the more recently discovered immune checkpoint proteins is V-domain Ig-containing suppressor of T cell activation (VISTA), which plays a crucial role in anti-cancer immune evasion pathways. The biochemical mechanisms underlying regulation of VISTA expression remain unknown. Here, we report for the first time that VISTA expression is controlled by the transforming growth factor beta type 1 (TGF-β)-Smad3 signaling pathway. However, in T lymphocytes, we found that VISTA expression was differentially regulated by TGF-β depending on their immune profile. Taken together, our results demonstrate the differential biochemical control of VISTA expression in human T cells and various types of rapidly proliferating cells, including cancer cells, fetal cells and keratinocytes

The history of slovenian political ideas

Slovenska politična misel je v širši zgodovini politološkega okolja razmeroma nova stvar. To ne bi smelo biti radikalno presenečenje, saj je v luči celotne evropske zgodovine tudi mnogo narodnih in nacionalnih identitet izjemno mladih – slovenska je ena izmed njih. Čeprav je bil program Zedinjena Slovenija le negotova preambula, so konflikti in premiki zgodnjega in srednjega 20. stoletja preoblikovali slovensko politično psiho in iz nje ustvarili rodovitna tla za vznik in razvoj narodnega vprašanja. Skozi to stoletje ideologije in oboroženih konfliktov smo spremljali velika imena slovenske politične zgodovine, kot so Lončar, Kidrič, Kocbek, Kardelj, Ude, Korošec in Bibič, ki so vsi pustili svoj pečat na narodnoosvobodilnem boju. Refleksija na Osvobodilno fronto (OF) in njene posledice nam lahko prikaže mnogo realnosti o pravih koreninah slovenstva in slovenske politične misliSlovenian political thought is a relatively new topic in the wider history of the political science environment. European history has also seen many ethnical and national identities that are very young, with Slovenia being one of them. Although the first Slovenian political programme called United Slovenia was only an uncertain preamble, conflicts and shifts in the early and middle 20th century transformed the Slovenian political psyche and created fertile soil for the birth and development of the ‘national question’. Throughout this century of ideology and armed conflict, we followed the great names in Slovenian political history, like Lončar, Kidrič, Kocbek, Kardelj, Ude, Korošec and Bibič, all of whom left their mark on the national liberation struggle. Reflections on Osvobodilna fronta (OF) and its consequences can tell us much about the true roots of Slovenianness and Slovenian political though

Nationalräkenskaper 1994, 1:a kvartalet

Suomen virallinen tilasto (SVT

Slovenski nacionalni interes iz zgodovinske retrospektive

Referat predstavlja poglede slovenskega naroda na svoj nacionalni interes v dolgem zgodovinskem loku od leta 1848, ko je slovenski narod postal politični dejavnik in je prvič jasno in glasno izrazil svoj zgodovinski interes, zedinjeno demokratično in avtonomno Slovenijo, pa vse do danes. V kronološkem zaporedju so predstavljene deklaracije slovenskega nacionalnega interesa številnih slovenskih političnih sil, strank in posameznikov različnih socialnih in ideoloških usmeritev, pri katerih pa je vedno živo zavedanje slovenskega narodnega interesa, njegovo programsko opredeljevanje v okviru vrhovne nacionalne paradigme, razvoj slovenskega naroda in vzpostavitev zedinjene avtonomne in nazadnje čisto svobodne Slovenije. Različne politične skupine so tej osnovni opredelitvi dajale še številne parcialne interese v skladu s svojim posebnim socialnim in ideološkim interesom. Referat kritično zavrača dezorientacijo vodilnih ljudi liberalne demokracije glede nacionalnegainteresa v zadnjem času.The article resumes positions of the Slovenian nation with regard to its national interest in a long historical retrospective from 1848 when the Slovenian nation became a political factor and expressed clearly and loudly for the first time its historical interest - a united democratic and autonomous Slovenia, until present day. In chronological order declarations ofSlovenian national interest are presented by numerous Slovenian political actors, parties and individuals of various social and ideological backgrounds in which one always discerns a lively awareness of Slovenian national interest, its program definition in the framework of the principal national paradigm, the development of the Slovenian nation and the establishment of a united, autonomous and finally independent Slovenia. Various political groups completed the basic definition with their partial interests in accordance withparticular social and ideological interests. The article critically rejects recent disorientation considering national interest of the leaders of Liberal Democratic Party

Cathepsin X activity does not affect NK-target cell synapse but is rather distributed to cytotoxic granules

Cathepsin X is a lysosomal peptidase that is involved in tumour progression and represents a potential target for therapeutic interventions. In addition, it regulates important functions of immune cells and is implicated in the modulation of tumour cell–immune cell crosstalk. Selective cathepsin X inhibitors have been proposed as prospective antitumour agents to prevent cancer progressionhowever, their impact on the antitumour immune response has been overlooked. Previous studies indicate that the migration and adhesion of T cells and dendritic cells are affected by diminished cathepsin X activity. Meanwhile, the influence of cathepsin X inhibition on natural killer (NK) cell function has not yet been explored. Here, we examined the localization patterns of cathepsin X and the role of its inhibitors on the cytotoxicity of cell line NK-92, which is used for adoptive cellular immunotherapy in cancer patients. NK-92 cells depend on lymphocyte function-associated antigen 1 (LFA-1) to form stable immunoconjugates with target cells, providing, in this way, optimal cytotoxicity. Since LFA-1 is a substrate for cathepsin X activity in other types of cells, we hypothesized that cathepsin X could disturb the formation of NK-92 immunoconjugates. Thus, we employed cathepsin X reversible and irreversible inhibitors and evaluated their effects on the NK-92 cell interactions with target cells and on the NK-92 cell cytotoxicity. We show that cathepsin X inhibition does not impair stable conjugate formation or the lytic activity of NK-92 cells. Similarly, the conjugate formation between Jurkat T cells and target cells was not affected by cathepsin X activity. Unlike in previous migration and adhesion studies on T cells, in NK-92 cells cathepsin X was not co-localized with LFA-1 at the plasma membrane but was, rather, redistributed to the cytotoxic granules and secreted during degranulation

Die rationalistische Zivilisation

Die letzten 225 Jahre in der Geschichte Europas kann als die Epoche der rationalistischen Zivilisation bezeichnet werden, der Zivilisation, die in der menschlichen Vernunft den Ursprung ihres ganzen Tuns begruendet. Gemaess dieser Grundannahme zeigt der Autor aus geschichtswissenschaftlicher Perspektive auf, wie die Menschen ihr Leben in der Geschichte vermittels ihrer Vernunft gestaltet haben bzw. wie die Menschen ihre Vernunft und den Platz derselben im Kosmos definierten. Des Weiteren wird das Verhaeltnis der Vernunft zur Metaphysik bzw. zur Religion und Moral betrachtet, weil diese beiden Bezugspunkte sehr wichtige Bereiche der menschlichen Interessen und Bestimmungen darstellen. Insgesamt gesehen verfolgt die Abhandlung das Ziel, die Vorstellungen ueber die menschliche Freiheit, Gleichheit, soziale Ordnung, Demokratie, den technischen und wirtschaftlichen Fortschritt, die Entfaltung des Nationalismus, die zwischenstaatlichen Beziehungen, die Entwicklung der Wissenschaft und Kunst zu beleuchten. Dabei gliedern sich die Ausfuehrungen in die folgenden Zeitabschnitte mit ihren entsprechenden Schwerpunkten: Die Epoche von 1775-1849 umfasst die Aspekte (1) Grundlagen der Aufklaerung, (2) den aufgeklaerten Absolutismus, (3) die Buergerliche Revolution in Frankreich und ihre ideologischen Folgen, (4) die Geburt des Nationalismus, (5) die Entwicklung der Wissenschaften, (6) die Romantik als Widerstand gegen den Rationalismus sowie (7) die Buergerliche Revolution in Mitteleuropa 1848/49. Die Epoche von 1850-1918 beinhaltet (1) die Dominanz des rationalistischen Liberalismus, (2) die Entwicklung des Sozialismus, (3) die antirationalistische Stellung der Kirche, (4) die Entwicklung der Wissenschaften bis zu ihrer Reife im 19. Jahrhundert, (5) die letzten Versuche der universalistisch-philosophischen Kosmosvorstellungen, (6) das buergerliche Lebensideal und (7) den katastrophalen Nationalismus. Die Epoche von 1919-1945 widmet sich (1) dem kurzlebigen Friedensoptimismus, (2) den antiliberalen und antidemokratischen Totalitarismen, (3) der Vielfalt der philosophischen und antirationalistischen Schulen, (4) der Entwicklung von Wissenschaft und Technologie, (5) der wirtschaftlichen und sozialen Entwicklung sowie (6) dem Nationalsozialismus. Die Epoche von 1945-2000 thematisiert schliesslich (1) die neue Ordnung der Nachkriegszeit, (2) das Schwinden des Transzendentalbewusstseins in der Philosophie, (3) den Einfluss der Wissenschaften, (4) Europas Primatverlust in der Wissenschaft und Politik, (5) die Veraenderungen im wirtschaftlichen, sozialen und kulturellen Leben, (6) die Wiederherstellung der europaeischen Einigkeit sowie (7) die Suche einer neuen geistigen Gestalt. (ICG2)SIGLEAvailable from Universitaet Bonn, Zentrum fuer Europaeische Integrationsforschung -ZEI-, Bonn (DE) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Increased cystatin F levels correlate with decreased cytotoxicity of cytotoxic T cells

Cystatin F is a protein inhibitor of cysteine peptidases, expressed predominantly in immune cells and localised in endosomal/lysosomal compartments. In cytotoxic immune cells cystatin F inhibits both the major pro-granzyme convertases, cathepsins C and H that activate granzymes, and cathepsin L, that acts as perforin activator. Since perforin and granzymes are crucial molecules for target cell killing by cytotoxic lymphocytes, defects in the activation of either granzymes or perforin can affect their cytotoxic potential