Adult hippocampal neurogenesis occurs in an exceptional permissive microenvironment. Neuroimmunological mechanisms might be prominently involved in the endogenous homeostatic principles that control baseline levels of adult neurogenesis. We show in this study that this homeostasis is partially dependent on CD4-positive T lymphocytes. Systemic depletion of CD4-positive T lymphocytes led to significantly reduced hippocampal neurogenesis, impaired reversal learning in the Morris water maze, and decreased brain-derived neurotrophic factor expression in the brain. No such effect of CD8 or B cells was observed. Repopulation of RAG2−/− mice with CD4, but not with CD8 cells again increased precursor cell proliferation. The T cells in our experiments were non-CNS specific and rarely detectable in the healthy brain. Thus, we can exclude cell-cell contacts between immune and brain cells or lymphocyte infiltration into the CNS as a prerequisite for an effect of CD4-T cells on neurogenesis. We propose that systemic CD4-T cell activity is required for maintaining cellular plasticity in the adult hippocampus and represents an evolutionary relevant communication route for the brain to respond to environmental changes.

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ABSTRACT

SUMMARY The genetic instability of cancer cells frequently causes drug resistance. We established mouse cancer models, which allowed targeting of an oncogene by drug-mediated inactivation or mono-specific CD8+ effector T (TE) cells. Drug treatment of genetically-unstable large tumors was effective but selected resistant clones in the long term. In contrast, TE cells completely rejected large tumors (≥500 mm3), if the target antigen was cancer-driving and expressed in sufficient amounts. While drug-mediated oncogene inactivation selectively killed the cancer cells and left the tumor vasculature intact, which likely facilitated survival and growth of resistant clones, TE cell treatment led to blood vessel destruction and probably “bystander” elimination of escape variants, which did not require antigen cross-presentation by stromal cells.

Activation of tumor-associated CD8+ cytotoxic T lymphocytes (CTLs) often requires antigen representation, e.g., by dendritic cells (DCs), and CD4+ T cell help. Previously, we showed that CTL-mediated tumor immunity required interleukin 4 (IL-4) during the immunization but not effector phase. To determine the source and target cells of IL-4, we performed adoptive T cell transfers using CD4+ and CD8+ T cells from IL-4−/− and IL-4R−/− mice and analyzed CTL generation. Even though necessary for CTL generation, CD4+ T cells did not need to express IL-4 or IL-4R. Surprisingly, CTL generation required IL-4 but not IL-4R expression by CD8+ T cells. As IL-4 (a) was expressed by naive CD8+ T cells within 24 h after antigen encounter, (b) IL-4 induced DC maturation, and (c) CTL development was impaired in T cell–reconstituted IL-4R−/− mice, CD8+ T cell–derived IL-4 appears to act on DCs. We conclude that CD4+ and CD8+ T cells provide different signals for DC activation during CTL generation.

MethodsStatistics. Independent 2-sample t test was used to evaluate statistical differences between R24C/R24L and AAG/ELA data sets. P < 0.05 was considered significant, P < 0.01 highly significant.Study approval. All animal experiments were performed according to institutional and national guidelines, after approval by the responsible authority (Landesamt für Gesundheit und Soziales, Berlin). Blood collection from healthy human donors was done after prior informed consent. A complete, detailed description of all methods is provided in Supplemental Methods.

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It has been shown that injecting a suspension of IFN-c-secreting tumor cells results in their rejection. This effect has been attributed to IFN-c preventing tumor stroma formation but not to a direct effect on the cancer cells. However, it is not known, which influence IFN-c has on tumors with an established stroma. To address this question, the plasmacytoma cell line J558L was transduced with a vector allowing doxycycline-inducible IFN-c gene expression.