Role of antigen, CD8, and cytotoxic T lymphocyte (CTL) avidity in high dose antigen induction of apoptosis of effector CTL

Experimental data suggest that negative selection of thymocytes can occur as a result of supraoptimal antigenic stimulation. It is unknown, however, whether, such mechanisms are at work in mature CD8+ T lymphocytes. Here, we show that CD8+ effector cytotoxic T lymphocytes (CTL) are susceptible to proliferative inhibition by high dose peptide antigen, leading to apoptotic death mediated by TNF-α release. Such inhibition is not reflected in the cytolytic potential of the CTL, since concentrations of antigen that are inhibitory for proliferation promote efficient lysis of target cells. Thus, although CTL have committed to the apoptotic pathway, the kinetics of this process are such that CTL function can occur before death of the CTL. The concentration of antigen required for inhibition is a function of the CTL avidity, in that concentrations of antigen capable of completely inhibiting high avidity CTL maximally stimulate low avidity CTL. Importantly, the inhibition can be detected in both activated and resting CTL. Blocking studies demonstrate that the CD8 molecule contributes significantly to the inhibitory signal as the addition of anti-CD8 antibody restores the proliferative response. Thus, our data support the model that mature CD8+ CTL can accommodate an activation signal of restricted intensity, which, if surpassed, results in deletion of that cell

Expression of the HPV16E7 Oncoprotein by Thymic Epithelium is Accompanied by Disrupted T Cell Maturation and a Failure of the Thymus to Involute with Age

Transgenic mice expressing the E7 protein of HPV16 from the keratin 14 promoter demonstrate increasing thymic hypertrophy with age. This hypertrophy is associated with increased absolute numbers of all thymocyte types, and with increased cortical and medullary cellularity. In the thymic medulla, increased compartmentalization of the major thymic stromal cell types and expansion of thymic epithelial cell population is observed. Neither an increased rate of immature thymocyte division nor a decreased rate of immature thymocyte death was able to account for the observed hypertrophy

Inactivation of human immunodeficiency virus (HIV)-1 envelope-specific CD8+ cytotoxic T lymphocytes by free antigenic peptide: A self-veto mechanism?

Free peptide has been found to inhibit cytotoxic T lymphocyte (CTL) activity, and veto cells bearing peptide-major histocompatibility complex (MHC) complexes have been found to inactivate CTL, but the two phenomenon have not been connected. Here we show that a common mechanism may apply to both CD8+ CTL lines or clones specific for a determinant of the human immunodeficiency virus (HIV)-1 IIIB envelope protein gp160, P18IIIB, are inhibited by as little as 10 min exposure to the minimal 10-mer peptide, 1- 10, within P18IIIB, free in solution, in contrast to peptide already bound to antigen-presenting cells (APC), which does not inhibit. Several lines of evidence suggest that the peptide must be processed and presented by H-2D(d) on the CTL itself to the specific T cell receptor (TCR) to be inhibitory. The inhibition was not killing, in that CTL, did not kill 51Cr-labeled sister CTL in the presence of free peptide, and in missing experiments with CTL lines of different specificities restricted by the same MHC molecule, D(d), the presence of free peptide recognized by one CTL line did not inhibit the activity of the other CTL, line that could present the peptide. Also, partial recovery of activity could be elicited by restimulation with cell-bound peptide, supporting the conclusion that neither fratricide nor suicide (apoptosis) was involved. The classic veto phenomenon was ruled out by failure of peptide-bearing CTL to inactivate others. Using pairs of CTL lines of differing specificity but similar MHC restriction, each pulsed with the peptide for which the other is specific, we showed that the minimal requirement is simultaneous engagement of the TCR and class I MHC molecules of the same cell. This could occur in single cells or pairs of cells presenting peptide to each other. Thus, mechanistically the inhibition is analogous to veto, and might be called self-veto. As a clue to a possible mechanism, we found that free 1-10 peptide induced apparent downregulation of expression of specific TCR as well as interleukin 2 receptor, CD69, lymphocyte function-associated antigen 1, and CD8. This self-veto effect also has implication for in vivo immunization and mechanisms of viral escape from CTL immunity

Unterhaltungsqualität und Public Value

Gebühren finanzierte TV Sender haben die Aufgabe Public Value zu schaffen. In der Regel umfasst der Leistungsauftrag dabei sowohl Information und Bildung als auch Unterhaltung. Während sich für informierende und bildende Inhalte relativ leicht feststellen lässt, worin der Nutzen für die Öffentlichkeit besteht, ist dies für die Unterhaltung weniger eindeutig. An dieser Stelle setzt der Beitrag an. Es wird argumentiert, dass der Public Value von Unterhaltung von der Qualität der Unterhaltung abhängt. Hierfür muss zunächst geklärt werden, an welchen Kriterien sich die Qualität von Unterhaltung festmachen lässt. Die Qualität stellt sich vielschichtig dar, es müssen unterschiedliche Perspektiven z.B. von Rezipienten, Produzenten und Regulierern berücksichtigt werden. Auf Basis einer Messung von Qualität wird in einen zweiten Schritt diskutiert, welche Unterhaltungsangebote einen Public Value aufweisen und welchen dieser fehlt, so dass sie nicht zu den Aufgaben eines Service Public Senders zu zählen sind. Dabei zeigt sich, dass eine absolute Bewertung nicht gerechtfertigt ist, sondern jeweils die Kontextbedingungen eines Medienmarkts berücksichtigt werden müssen. Anhand von konkreten Unterhaltungsangeboten von europäischen Service Public Anbietern wird die Messung von Qualität illustriert und mit den Kontextbedingungen in Bezug gesetzt

Ploidy elicits a whole-genome dosage effect: growth of triploid Atlantic salmon is linked to the genetic origin of the second maternal chromosome set

publishedVersio

HPV vaccines: the beginning of the end for cervical cancer

Vaccines prophylactic against infection with human papillomavirus (HPV) are based on alum adjuvanted virus-like particles. Two such vaccines have recently been shown to prevent persistent HPV infection and associated cervical cancer precursor lesions. The genotype-specific neutralising antibody directed at conformational epitopes of the L1 major capsid protein is likely to mediate protection. Vaccines therapeutic for persisting HPV infection can eliminate transplantable tumors in animal models, but are of limited efficacy in mice grafted with skin that expresses HPV antigens or in humans. This paradox has been partially resolved by data clarifying the immunoregulatory role of skin cytokines (e.g. transforming growth factor-beta and interleukin-10) and the consequences of antigen presentation by subsets of skin-associated antigen-presenting cells