Immune cells cannot easily cross the blood-brain barrier to enter the central nervous system. But when they do reach the brain to fight infection, they don’t let go, according to research published October 5 in the Proceedings of the National Academy of Sciences. Pathogen-specific T cells remain on guard in the brains of mice, quite possibly for the life of the animal, said senior author Michael Bevan of the University of Washington in Seattle. The work, led by first author Linda Wakim, also in Seattle, is basic science research but could have implications for neuroinflammation and neurodegenerative disease.

There are a few places in the body—such as the skin, sensory ganglia, and gut—where T cells, once activated, stick around the infection site to watch for future outbreaks (Wakim et al., 2008; Masupust et al., 2010). These are known as resident memory T cells (Trms). For example, Trm cells specific for herpes simplex virus 1 (HSV1) remain in sensory ganglia, ready to go when the latent virus re-emerges to cause a cold sore (Gebhardt et al., 2009; Khanna et al., 2003).

The brain is a largely immuno-privileged site. Circulating immune cells and antibodies normally stay on the blood side of the blood-brain barrier. But during infection, the barrier weakens, allowing immune cells to squeeze through and battle the pathogen. The current study adds the brain to the short list of tissues where Trm cells persist long after infection has subsided.

“Evolution’s rationale,” Bevan said, “is to assume that this is a latent or chronic infection.” If the pathogen were hiding in the nerves—as, for example, HSV1 does—lurking at the former hotspot would position T cells to ambush any virus attempting to reactivate.

To study Trms in the brain, Wakim seeded mice with T cells specific for ovalbumin. Then, she infected the mice with recombinant vesicular stomatitis virus that expressed the ovalbumin antigen as well as green fluorescent protein. She used inhalation; that way, the virus could reach the brain via the olfactory system.

Three days after infection, histological analysis confirmed that the virus clustered in “hotspots” throughout the brain. Within a month, T cells had surrounded and destroyed the last of the virus. However, those ovalbumin-specific T cells did not pack it in after a job well done. They remained, inactive, in cluster formations—presumably around former viral hotspots—for at least 120 days. They also expressed the integrin CD103, which is known to bind to the cadherin expressed by epithelial cells. The researchers suspect CD103 has a binding partner in the brain that allows it to latch on to former viral hotspots. Knocking down CD103 expression reduced Trm cell retention in the brain.

Wakim attempted to isolate Trm cells from the brain to transfer into another animal. It is a technique that normally works with other T cell populations, but the brain T cells died in culture and failed to mount an immune response in their new hosts. “They have somehow become dependent on the brain environment for their survival,” Bevan concluded. The researchers are using microarrays to compare brain Trms to other T cells, looking for factors that might explain the unusual dependence on the brain environment.

Some scientists are proposing that microbial pathogens may influence neurodegeneration, though this is not universally accepted. Research suggests that infection—for example, by HSV1—might predispose the brain to Alzheimer disease (reviewed in Wozniak and Itzhaki, 2010). In another example, avian flu can trigger Parkinson’s-like symptoms in mice (see ARF related news story on Jang et al., 2009; see also ARF Live Discussion). Scientist do agree that neuroinflammation appears in many neurodegenerative conditions (see ARF related news story on Saijo et al., 2009 and ARF related news story on Meissner et al., 2010).

“It is important to consider that these brain-resident T cells could be problematic, because they persist in an environment not accustomed to routine immune surveillance or immune tolerance,” the authors write. Could Trm cells contribute to neurodegeneration? It is too soon to tell, Bevan said. In the meantime, he speculated that inflammation in the aging brain might reactivate dormant Trm cells from prior infections, in which case they could further fan the flames of neuroinflammation.—Amber Dance


  1. Joseph Prandota at the University Medical School in Wroclaw, Poland, suggests that Toxoplasma gondii (T. gondii), the parasitic protozoa hosted in cats, which causes cerebral toxoplasmosis (CT), may be implicated in the pathogenesis of Alzheimer's disease (AD).

    Prandota states that T. gondii affects chromatin structure and may cause dysregulation of the host cell cycle. Moreover, it seems that the accumulation of iron in senile plaques reflects a defense of the host against T. gondii because this transition metallic ion is necessary for proliferation of tachyzoites, which are part of the protozoan's life cycle.

    Prandota observes that the beneficial effects of ibuprofen in patients with AD, which restored cellular immunity, decreased production of proinflammatory cytokines, nitric oxide, and amyloid-β, and reduced lipid peroxidation and free radical generation, are consistent with the suggestion that congenital and/or acquired chronic latent CT plays a role in neurodegeneration.


    . Metabolic, immune, epigenetic, endocrine and phenotypic abnormalities found in individuals with autism spectrum disorders, Down syndrome and Alzheimer disease may be caused by congenital and/or acquired chronic cerebral toxoplasmosis. Res Autism Spectr Disord. 2011 Jan-Mar;5(1):14-59.

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News Citations

  1. Bugs on the Brain—Can Flu Cause Parkinsonism, Neurodegeneration?
  2. Out-of-Control Inflammation in Parkinson's: It's Glia, Again
  3. Mutant SOD1 Inflames If Not Quenched by Autophagy

Webinar Citations

  1. The Pathogen Hypothesis—Challenging the Primacy of Genetics in Late-Onset Alzheimer Disease.

Paper Citations

  1. . Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science. 2008 Jan 11;319(5860):198-202. PubMed.
  2. . Dynamic T cell migration program provides resident memory within intestinal epithelium. J Exp Med. 2010 Mar 15;207(3):553-64. PubMed.
  3. . Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol. 2009 May;10(5):524-30. PubMed.
  4. . Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia. Immunity. 2003 May;18(5):593-603. PubMed.
  5. . Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14063-8. PubMed.
  6. . A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell. 2009 Apr 3;137(1):47-59. PubMed.
  7. . Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13046-50. PubMed.

External Citations

  1. Wozniak and Itzhaki, 2010

Further Reading


  1. . Immunohistological detection of Chlamydia pneumoniae in the Alzheimer's disease brain. BMC Neurosci. 2010;11:121. PubMed.
  2. . Five-year survival after Helicobacter pylori eradication in Alzheimer disease patients. Cogn Behav Neurol. 2010 Sep;23(3):199-204. PubMed.
  3. . Neuroimmune pharmacology of neurodegenerative and mental diseases. J Neuroimmune Pharmacol. 2011 Mar;6(1):28-40. PubMed.
  4. . HSV-1 promotes Ca2+ -mediated APP phosphorylation and Aβ accumulation in rat cortical neurons. Neurobiol Aging. 2011 Dec;32(12):2323.e13-26. Epub 2010 Jul 31 PubMed.
  5. . Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol. 2010 Sep;120(3):277-86. PubMed.
  6. . Erythropoietin plus insulin-like growth factor-I protects against neuronal damage in a murine model of human immunodeficiency virus-associated neurocognitive disorders. Ann Neurol. 2010 Sep;68(3):342-52. PubMed.

Primary Papers

  1. . Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence. Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):17872-9. PubMed.