In situ transduction of stromal cells and thymocytes upon intrathymic injection of lentiviral vectors

BACKGROUND: The thymus is the primary site for T-cell development and induction of self-tolerance. Previous approaches towards manipulation of T-cell differentiation have used intrathymic injection of antigens, as proteins, cells or adenoviruses, leading to transient expression of the foreign protein. Lentiviral vectors, due to their unique ability to integrate into the genome of quiescent cells, may be best suited for long-term expression of a transgene in the thymus. RESULTS: Young adult mice were injected in the thymus with lentiviral vectors expressing eGFP or the hemaglutinin of the Influenza virus under the control of the ubiquitous phospho glycerate kinase promoter. Thymi were examined 5 to 90 days thereafter directly under a UV-light microscope and by flow cytometry. Intrathymic injection of lentiviral vectors predominantly results in infection of stromal cells that could be detected for at least 3 months. Importantly, hemaglutinin expression by thymic stromal cells mediated negative selection of thymocytes expressing the cognate T-cell receptor. In addition and despite the low multiplicity of infection, transduced thymocytes were also detected, even 30 days after injection. CONCLUSIONS: Our results demonstrate that intrathymic delivery of a lentiviral vector is an efficient means for stable expression of a foreign gene in the thymus. This new method of gene delivery may prove useful for induction of tolerance to a specific antigen and for gene therapy of severe combined immunodeficiencies

Interleukin-1 in the Response of Follicular Helper and Follicular Regulatory T Cells

The role of interleukin-1 in the regulation of humoral responses is poorly documented, in contrast to its role in inflammation. Recent findings suggest there is an interleukin-1 axis in the follicular T cell control of B cell responses, involving interleukin-1 receptors (IL-1R1 and IL-1R2) and receptor antagonists (IL-1Ra). Here, we revisit the literature on this topic and conclude that targeting the interleukin-1 pathway should be a valuable therapeutic approach in many diseases involving excessive production of (auto)antibodies, such as autoimmune diseases or allergy

Économie et géographie de l’agriculture

Joseph Klatzmann, directeur d’études Les pièges de la statistique L’enseignement a porté, comme les années précédentes, sur les pièges de la statistique, de toutes natures et dans tous les domaines. La méthode a consisté à faire réfléchir les étudiants sur des exemples trouvés dans des journaux, des articles ou des ouvrages. Un cas typique d’erreur grossière est celui du titre d’article faux parce qu’on a voulu le raccourcir : « la productivité a diminué dans l’industrie » au lieu de « le tau..

Économie et géographie de l’agriculture

Joseph Klatzmann, directeur d’études Les pièges de la statistique Pour attirer l’attention des étudiants sur les très nombreux problèmes d’interprétation des statistiques, on les fait réfléchir sur des exemples réels, tirés principalement de la presse, d’ouvrages et d’autres médias. Dans la première période, les exemples soumis à la réflexion des étudiants ont été classés en fonction des différents types de pièges ; dans la deuxième, ils l’ont été par matières : démographie, économie, etc. Un..

Économie et géographie de l’agriculture

Joseph Klatzmann, directeur d’études Les pièges de la statistique Un moyen efficace (il y en a aussi d’autres) d’informer les étudiants de tous les pièges dont ils doivent se méfier en lisant des données statistiques est de les faire réfléchir sur des articles de presse et des extraits d’ouvrages. Cette analyse a aussi pour but d’attirer leur attention sur les précautions à prendre lorsqu’ils doivent eux-mêmes présenter des statistiques. Voici quelques exemples des problèmes qui ont été discu..

Antigen quality determines the efficiency of antitumor immune responses generated in the absence of regulatory T cells

The observation that depletion or inhibition of regulatory T cells (Tregs) unleashes efficient antitumor effector immune responses that can lead to tumor eradication in mice has opened new perspectives for the development of cancer immunotherapy. The quality and overall efficiency of the effector immune responses induced in the absence of Tregs seem to depend on multiple factors that determine the result of a battle involving effector T cells (Teffs), Tregs and tumor cells. In this study, we investigated the quality of tumor-associated antigens (TAAs) as one such factor. We show that the presence of a strong dominant antigen is required for the induction of effector responses capable of tumor eradication in the absence of Tregs. The sole addition of a dominant antigen on tumor cells does not change tumor growth in unmanipulated mice, but improves tumor eradication rate from a few to almost 100% in the absence of Tregs. This eradication can be shown to result from the recruitment and activation of specific Teffs recognizing this antigen. We also show that the presence of such dominant antigens has the side effect of restricting the breadth of the immune response to other TAAs, which could favor the generation of escape mutant by tumor editing. Taken together, our results highlight the potential, and some requirements for cancer immunotherapy based on Treg depletion. They also show that, ultimately, tumor fate depends on multiple factors that should all be taken into consideration for the design of more efficient immunotherapy

CD4+CD25+ Immunoregulatory T Cells: New Therapeutics for Graft-Versus-Host Disease

CD4+CD25+ immunoregulatory T cells play a pivotal role in preventing organ-specific autoimmune diseases and in tolerance induction to allogeneic organ transplants. We investigated whether these cells could also control graft-versus-host disease (GVHD), the main complication after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we show that the few CD4+CD25+ T cells naturally present in the transplant regulate GVHD because their removal from the graft dramatically accelerates this disease. Furthermore, the addition of freshly isolated CD4+CD25+ T cells at time of grafting significantly delays or even prevents GVHD. Ex vivo–expanded CD4+CD25+ regulatory T cells obtained after stimulation by allogeneic recipient-type antigen-presenting cells can also modulate GVHD. Thus, CD4+CD25+ regulatory T cells represent a new therapeutic tool for controlling GVHD in allogeneic HSCT. More generally, these results outline the tremendous potential of regulatory T cells as therapeutics