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

• 成果类型: Article
• 署名作者: Porte, Remi; Belloy, Marcy; Audibert, Alexis; Bassot, Emilie; Aida, Amel; Alis, Marine; Miranda-Capet, Romain; Jourdes, Aurelie; van Gisbergen, Klaas P. J. M.; Masson, Frederick; Blanchard, Nicolas
• 署名单位: Universite de Toulouse; Universite Toulouse III - Paul Sabatier; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); Fundacao Champalimaud
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10917
• DOI: 10.1073/pnas.2403054121
• 发表日期: 2024-06-11
• 关键词: memory t-cells; nonlymphoid tissue; infection; expression; effector; exhaustion; parasite; persistence; program; PATHWAY

摘要

Chronic 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.