CD4-Positive T Lymphocytes Provide a Neuroimmunological Link in the Control of Adult Hippocampal Neurogenesis

Abstract

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.

Myelin-specific T helper 17 cells promote adult hippocampal neurogenesis through indirect mechanisms

“…TCRα +/– mice (11469 ± 273, n = 7) ranged between controls and knockouts. Overall, these results are in agreement with our previous observation that CD4 + T cells provide a neuro-immunological link in the base-line regulation of hippocampal precursor cell activity 6 .…”

“…Mechanistically, and consistent with the proneurogenic activity of non-infiltrating CD4 + T cells with a polyclonal TCR repertoire 6, 7 , the overall absence of immune cell infiltrations in our Th17 adoptive transfer model emphasizes that direct cell-cell interaction is not a prerequisite of enhanced Th17-mediated hippocampal precursor cell proliferation. Alternatively, Th17 cells residing in peripheral lymphoid tissues outside the brain may secrete cytokines that are actively transported across the blood-brain barrier 45, 46 and act on the hippocampal neurogenic niche to promote precursor cell proliferation.…”

“…However the molecular and cellular mechanisms underlying CD4 + T cell-mediated enhancement of adult neurogenesis have largely remained unclear. For example, whether or not the infiltration of myelin-reactive T cells into the CNS is a prerequisite for the proneurogenic activity of CD4 + T cells has been controversially discussed 5, 6, 8, 9 . Additionally, the relative contribution of the activation or differentiation status of the CD4 + T cells to their proneurogenic activity remains to be determined.…”

CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging

“…1A). Because CD4 + T cells (rather than CD8 + cells) were previously implicated in supporting CNS plasticity (1,2,8,12), we further characterized this subpopulation. We focused our interest on memory T cells, commonly divided into two subsets ( Fig.…”

The emergence of a new science of the mind: immunology benefits the mind

“…Likewise, the fields of neuroimmunology and psychoneuroimmunology have evolved from disciplines that view the cross-talk between the peripheral immune system and the brain either in terms of how the mind affects the immune system 1 or in terms of how immune system pathologies (such as inflammation) disrupt the mind, 2,3 to fields that appreciate the pivotal role of circulating immune cells in helping sustain the healthy brain. [4][5][6][7] Thus, for example, it has been commonly accepted that mental stress (depending on its severity) either harnesses immune cells to support the body's function (excluding that of the brain) or suppresses healing; 8 however, the possibility that circulating immune cells may actually protect the brain's function from the consequences of stress was only recently recognized. 9,10 (Cover page) The novel dimensions that were identified in the cross-talk between the brain and the immune system are focused on understanding how the peripheral immune system contributes to brain plasticity, and in cases of brain pathologies, to reveal how immune insufficiency deprives the brain of necessary assistance required for normal behavior, cognition, mental activity and repair.…”