20 January 2006. Raging autoimmune T cells were fingered as the culprits in the toxicity of the failed first-generation Alzheimer disease (AD) vaccine. Even so, one research group suggests that some alleged immune attackers could turn out to have a softer, more nurturing side. If a paper published online in Nature Neuroscience on January 15 receives independent confirmation, then T cells might yet turn out to give critical support to the process of neurogenesis in the hippocampus of adult mice. In the new work, Michal Schwartz and colleagues from the Weizmann Institute of Science in Rehovot, Israel, show that the absence of T cells in two mouse immunodeficiency models is associated with lower levels of neurogenesis as measured by bromodeoxyuridine incorporation in vivo. Transfusions of T cell-rich spleen cells from normal mice reversed the deficit. Transgenic mice that have a surfeit of central nervous system-directed immune cells (in the form of myelin-reactive T cells) displayed more active neurogenesis, and better performance in a spatial learning and memory task compared to wild-type controls. Increased neurogenesis was accompanied by microglial activation and expression of brain-derived neurotrophic factor in these mice. At this point, the paper is not directly relevant to AD, as current data on AD and neurogenesis remain preliminary.
The new work appears to support Schwartz’s proposal, based on her previous work, that well-behaved, self-directed T cells confer a “protective autoimmunity” that can promote the health and repair of the nervous system. In this scheme, beneficial activation of microglia by T cell cytokines leads to the production of neurotrophic factors. But this idea is controversial, especially as it relates to the proclivities of myelin-reactive T cells. Schwartz and colleagues report that these cells ameliorate the effects of spinal cord injury (Hauben et al., 2000), where others find just the opposite (see ARF related news story). Few laboratories have as yet found corroborative evidence for Schwartz’s hypothesis, and the present paper cites a preponderance of her own papers as prior evidence. Even so, the new work provides additional evidence for some involvement of T cells in beneficial interactions with the nervous system. Much of that evidence is indirect at this stage, but the paper should serve to fuel interest in the role of the peripheral immune system, and particularly CNS-directed T cells, in neurodegeneration and repair.
Work by Fred Gage and colleagues previously showed that the birth of new neurons in the dentate gyrus of rat hippocampus could be stimulated in an enriched environment (Kempermann et al., 1997). In the current paper, dual first authors Yaniv Ziv and Noga Ron used this paradigm to search for a role for T cells in the process. Rats that were kept in plain accommodations, or treated to more stimulating cages, were dosed with BrdU to label dividing cells, and then killed after one week. Staining hippocampi with an anti-BrdU antibody showed a significant increase in cells labeled with both BrdU and the neuronal marker NeuN. The number of microglia was also increased, and a subset displayed some evidence of activation by T cell cytokines, with enhanced expression of MHC class II and insulin-like growth factor. The additional observation of the occasional T cell in the brain parenchyma suggested the hypothesis that T cells could influence the brain environment, perhaps rendering it more conducive to neurogenesis.
To further probe the connection between T cells and neuron birth, the researchers employed a novel strategy of studying hippocampal neurogenesis in two immunodeficient strains of mice. The severe combined immunodeficiency (SCID) mouse and the nude mouse both lack T cells. Both exhibited lower levels of neurogenesis compared to wild-type strain-matched mice, as measured by the detection of cells positive for both BrdU and NeuN or doublecortin in the hippocampus. In either strain, transfer of T cell-containing spleen preparations enhanced neurogenesis. T cells seemed to be required for the response to environment, since enrichment failed to increase neurogenesis in SCID mice, in contrast to its positive effect on immunocompetent mice.
If T cells in the CNS promote neurogenesis, then mice with many CNS-directed T cells might be particularly well endowed with new neurons. The authors tested this hypothesis by comparing two strains of mice transgenic for T cell receptor genes. One strain carries a transgene for a T cell receptor against myelin basic protein (TMBP), and 98 percent of the animal’s T cells are myelin-reactive. The other strain (TOVA) carries an ovalbumin-specific T cell receptor transgene. The TMBP mouse had significantly more BrdU/DCX double-labeled cells than its strain-matched control, while the TOVA mice had far fewer. The enhancement in TMBP mice seemed to be mediated by microglia, since the inhibitor minocycline reduced the level of neurogenesis. The authors showed no direct measurement or localization of T cells in the brain, so exactly how T cells might mediate this effect is unclear.
Finally, to assess behavioral correlates of neurogenesis, the researchers tested TMBP and TOVA mice in the Morris water maze, a spatial learning and memory test that requires hippocampal input. In all aspects of the water maze, the TMBP mice performed better than their matched controls, while the TOVA mice performed worse. BDNF levels correlated with the water maze results: The TMBP mice had higher levels of BDNF derived from neurons, while the TOVA or SCID had lower levels.
Given that the peripheral immune system can inhibit neurogenesis in the brain via inflammation, the idea that immune cells could also promote neurogenesis in some instances may not be such a surprise. The effects of immunodeficiency and T cell replenishment on neurogenesis in this study are consistent with just such a role. The data do not unequivocally show that T cells are responsible for the neurogenesis. More work will be required to test this intriguing hypothesis, and to ultimately determine how the peripheral immune system can best be manipulated to treat neurodegenerative disease.—Pat McCaffrey.
Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci. 2006 Jan 15; [Epub ahead of print] Abstract