Brain Microenvironment Promotes the Final Functional Maturation of Tumor-Specific Effector CD8 + T Cells

International audienc

Brain Microenvironment Promotes the Final Functional Maturation of Tumor-Specific Effector CD8 + T Cells

International audienc

Approches critiques de la sécurité

Face aux discours post-11 septembre sur la nécessité de la "guerre au terrorisme", développer des approches critiques contre cette voie à sens unique où le champ de la sécurité se trouve réduit à sa dimension militaire classique, s'impose comme une urgence. Ce numéro propose d'ouvrir des perspectives telles que celles de l'environnement et du genre. Un numéro dirigé par une équipe canadienne et basé sur d'intenses échanges transatlantiques. Given the post-September 11th discourse on the necessity of the “war against terrorism’, it is urgent that critical approaches are developed to combat this one-way street, in which security is reduced to only its military dimensions. This new issue of the journal Cultures & Conflits proposes to open up other perspectives, such as those of the environment or of gender. In positioning the issue within the field of theories of international relations, the authors of this issue move the focus onto the research currently being carried out, with varying and/or new perspectives. They feed debates beyond existing and imposed boundaries. Produced by a team led by Professor Macleod from the University of Quebec at Montreal (UQAM), and the result of intense transatlantic exchanges, this issue also wishes to make a contribution to theoretical debates about the role, normative claims, place, and pertinence of classical internationalist approaches, through the use of constructive criticism and a neo-gramscian approach

Cutting Edge: Cross-Presentation as a Mechanism for Efficient Recruitment of Tumor-Specific CTL to the Brain

International audienc

Protective function and differentiation cues of brain-resident CD8+ T cells during surveillance of latent Toxoplasma gondii infection

International audienceChronic Toxoplasma gondii infection induces brain-resident CD8+ T cells (bTr), but the protective functions and differentiation cues of these cells remain undefined. Here, we used a mouse model of latent infection by T. gondii leading to effective CD8+ T cell–mediated parasite control. Thanks to antibody depletion approaches, we found that peripheral circulating CD8+ T cells are dispensable for brain parasite control during chronic stage, indicating that CD8+ bTr are able to prevent brain parasite reactivation. We observed that the retention markers CD69, CD49a, and CD103 are sequentially acquired by brain parasite–specific CD8+ T cells throughout infection and that a majority of CD69/CD49a/CD103 triple-positive (TP) CD8+ T cells also express Hobit, a transcription factor associated with tissue residency. This TP subset develops in a CD4+ T cell–dependent manner and is associated with effective parasite control during chronic stage. Conditional invalidation of Transporter associated with Antigen Processing (TAP)-mediated major histocompatibility complex (MHC) class I presentation showed that presentation of parasite antigens by glutamatergic neurons and microglia regulates the differentiation of CD8+ bTr into TP cells. Single-cell transcriptomic analyses revealed that resistance to encephalitis is associated with the expansion of stem-like subsets of CD8+ bTr. In summary, parasite-specific brain-resident CD8+ T cells are a functionally heterogeneous compartment which autonomously ensure parasite control during T. gondii latent infection and which differentiation is shaped by neuronal and microglial MHC I presentation. A more detailed understanding of local T cell–mediated immune surveillance of this common parasite is needed for harnessing brain-resident CD8+ T cells in order to enhance control of chronic brain infections

Immune Infiltration of Spontaneous Mouse Astrocytomas Is Dominated by Immunosuppressive Cells from Early Stages of Tumor Development

International audienceImmune infiltration of advanced human gliomas has been shown, but it is doubtful whether these immune cells affect tumor progression. It could be hypothesized that this infiltrate reflects recently recruited immune cells that are immediately overwhelmed by a high tumor burden. Alternatively, if there is earlier immune detection and infiltration of the tumor, the question arises as to when antitumor competency is lost. To address these issues, we analyzed a transgenic mouse model of spontaneous astrocytoma (GFAP-V(12)HA-ras mice), which allows the study of immune interactions with developing glioma, even at early asymptomatic stages. T cells, including a significant proportion of Tregs, are already present in the brain before symptoms develop, followed later by macrophages, natural killer cells, and dendritic cells. The effector potential of CD8 T-cells is defective, with the absence of granzyme B expression and low expression of IFN-gamma, tumor necrosis factor, and interleukin 2. Overall, our results show an early defective endogenous immune response to gliomas, and local accumulation of immunosuppressive cells at the tumor site. Thus, the antiglioma response is not simply overwhelmed at advanced stages of tumor growth, but is counterbalanced by an inhibitory microenvironment from the outset. Nevertheless, we determined that effector molecule expression (granzyme B, IFN-gamma) by brain-infiltrating CD8 T-cells could be enhanced, despite this unfavorable milieu, by strong immune stimuli. This potential to modulate the strong imbalance in local antiglioma immunity is encouraging for the development and optimization of future glioma immunotherapies. (C)2010 AACR