• References

    Brombacher TM et al. (2017). IL-13-mediated regulation of learning and memory. J Immunol 198, 2,681-2,688.

    Brynskikh A et al. (2008). Adaptive immunity affects learning behavior in mice. Brain Behav Immun 22, 861-869.

    Derecki NC et al. (2010). Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207,1,067-1,080.

    Kipnis J et al. (2002). Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. PNAS 99,15,620-15,625.

    Kipnis J et al. (2004). T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. PNAS 101, 8,180-8,185.

    Serre-Miranda C et al. (2014). Effector memory CD4(+) T cells are associated with cognitive performance in a senior population. Neurology, neuroimmunol neuroinflamm 2, e54.

    Serpe CJ et al. (1999). Exacerbation of facial motoneuron loss after facial nerve transection in severe combined immunodeficient (scid) mice. J Neurosci 19, RC7.

    Stamatovic SM et al. (2016). Junctional proteins of the blood-brain barrier: new insights into function and dysfunction. Tissue Barriers 4, e1154641.

    van Langelaar J et al. (2020). B and T Cells driving multiple sclerosis: identity, mechanisms and potential triggers. Front immunol 11, 760.

    Wolf SA et al. (2009). CD4-positive T lymphocytes provide a neuroimmunological link in the control of adult hippocampal neurogenesis. J Immunol 182, 3,979-3,984.

    Yilmaz G et al. (2006). Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation 113, 2,105-2,112.

A T Cell for Your Thoughts?

22 January, 2021
A T Cell for Your Thoughts?

T cells, with their many functional subsets, are key mediators of the adaptive immune system. They are well-known for their targeted responses against both intra- and extra-cellular pathogens, tumors, and other perceived threats. However, outside of host protection, growing evidence suggests that T cells contribute to the regulation and homeostasis of a variety of body systems, including the central nervous system. But can they really influence our brain function? In this guest blog, we explore the contribution of T cells to learning and memory.

A Privileged Brain

The brain is the central coordinating system of the body and is a highly vascularized organ. Due to its critical functions, the brain needs extra protection from outside threats that may enter through the blood. One safeguard comes from the blood-brain barrier (BBB), which tightly controls the infiltration of substances through a network of endothelial cell tight junctions, pericytes, and astrocytic feet (Stamatovic et al. 2016). Because the BBB is so strict, it also greatly limits the migration of circulating leukocytes, including T cells, into the brain. Thus, the brain has long been considered a relatively immune privileged site, with its own resident immune cells, microglia.

However, damage to the BBB, such as traumatic brain injury and ischemic stroke allows the entrance of immune cells into the brain. In particular, T cells appear to play an important role in both repair and damage in these conditions. To help “rebuild” after an injury, they are recruited to the injury site and produce important neurotrophic factors that support the growth and survival of neurons (Kipnis et al. 2002). Severe combined immunodeficient (SCID) mice, which lack functional T cells and B cells, showed impaired neuronal survival following an injury compared to wild-type mice (Serpe et al. 1999). However, if T cell containing splenocytes are adoptively transferred into SCID mice, the neuronal death is attenuated. Yet T cells in the brain can also contribute to damaging neuroinflammation. In ischemic reperfusion injury models, lymphocyte deficient Rag−/− mice showed decreased lesion volumes compared to injured wild-type controls (Yilmaz et al. 2006). Similarly, neurodegenerative diseases, such as multiple sclerosis, are characterized by increased BBB permeability and influx of T cells (van Langelaar et al. 2020) which then attack the central nervous system and contribute to multiple sclerosis brain lesions. T cells, therefore, play both beneficial and detrimental roles in the injured and diseased brain.

T Cells on the Mind

Under normal physiologic conditions, a significant number of T cells do not typically enter the brain parenchyma despite appearing to be necessary to maintain regular cognitive functions. For example, the Morris water maze is a behavioral test that consists of a hidden platform in a pool of water. Mice swim around the pool and learn to find the platform in a certain quadrant over a series of trials, testing their spatial learning and memory. Unlike wild-type mice, SCID mice often fail to recall previous training, demonstrating decreased spatial learning and memory (Kipnis et al. 2004, Brynskikh et al. 2008). As SCID mice lack both T cells and B cells, Kipnis et al. (2004) confirmed the importance of T cells over B cells in memory. Morris water maze performance was significantly improved in nude mice reconstituted with T cells, compared to nude mice that lacked T cells but not B cells.

Interestingly, it appears that CD4+ T cells, also known as helper T cells, could play a particularly crucial role in learning and memory. When T cell deficient mice were reconstituted with CD4+ or CD8+ T cells, only CD4+ T cells increased neurogenesis in the hippocampus (Wolf et al. 2009). The hippocampus is a brain region key for memory formation which is degraded in diseases associated with memory decline, like Alzheimer’s disease. Mice treated with antibodies to deplete CD4+ T cells also showed declines in learning and memory behaviors in the Morris water maze. The impact of CD4+ involvement in memory also correlates with human cognitive performance as well. Levels of CD4+ T cells strongly correlate with cognitive performance in a cohort of 114 healthy, elderly adults (Serre-Miranda et al. 2014). Yet unlike the previously described mouse studies, CD4+ T cells were associated with poorer cognitive performance. However, the cohort study did not test spatial learning and memory like the Morris water maze test.

But if T cells don’t normally enter the brain parenchyma, how can they influence memory? The answer likely comes from the large number that populate the meninges – a three-layered membrane that envelops the brain and spinal cord and circulates cerebrospinal fluid. As T cells are notorious cytokine producers, paracrine signaling is likely to be how they influence the brain even under nonpathologic conditions. A strong example of the role of meningeal T cell cytokines in learning and memory is IL-4. Largely produced by CD4+ Th2 T cells, this anti-inflammatory cytokine accumulates in the meninges of mice after Morris water maze trials (Derecki et al. 2010). When IL-4 knockout mice were tested with the Morris water maze, their performance was significantly impaired. However, when IL-4 was replenished, learning and memory improved. Similarly, IL-13, another cytokine produced by Th2 T cells, also decreases Morris water maze performance (Brombacher et al. 2017). Additionally, T cell produced cytokines, such as IFNγ, IL-10, and IL-17 could influence various aspects of behavior, learning, and memory. Thus, a combination of various cytokines, likely from CD4+ T cells, is likely to be necessary for proper cognitive functioning.

What’s in a Memory

T cells have complex roles in the brain, appearing to contribute to both positive and negative outcomes in health and disease. As meningeal T cells not only produce cytokines, but also other substances such as growth factors and neuropeptides, the functional scope of these immune cells are likely to expand in the coming years. So perhaps the next time you forget where you put your phone, misremember a name, or accidentally skip an appointment, you can blame it on your T cells.

Studying T Cells?

Bio-Rad has a range of T cell markers and resources to support your research.

References

Brombacher TM et al. (2017). IL-13-mediated regulation of learning and memory. J Immunol 198, 2,681-2,688.

Brynskikh A et al. (2008). Adaptive immunity affects learning behavior in mice. Brain Behav Immun 22, 861-869.

Derecki NC et al. (2010). Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207,1,067-1,080.

Kipnis J et al. (2002). Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. PNAS 99,15,620-15,625.

Kipnis J et al. (2004). T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. PNAS 101, 8,180-8,185.

Serre-Miranda C et al. (2014). Effector memory CD4(+) T cells are associated with cognitive performance in a senior population. Neurology, neuroimmunol neuroinflamm 2, e54.

Serpe CJ et al. (1999). Exacerbation of facial motoneuron loss after facial nerve transection in severe combined immunodeficient (scid) mice. J Neurosci 19, RC7.

Stamatovic SM et al. (2016). Junctional proteins of the blood-brain barrier: new insights into function and dysfunction. Tissue Barriers 4, e1154641.

van Langelaar J et al. (2020). B and T Cells driving multiple sclerosis: identity, mechanisms and potential triggers. Front immunol 11, 760.

Wolf SA et al. (2009). CD4-positive T lymphocytes provide a neuroimmunological link in the control of adult hippocampal neurogenesis. J Immunol 182, 3,979-3,984.

Yilmaz G et al. (2006). Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation 113, 2,105-2,112.

 

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