Scientists in Portugal led by Julie Ribot and Bruno Silva-Santos, Universidade de Lisboa, report that a gaggle of specialized T cells hide out in the meninges of the healthy mouse brain, where they support both synaptic plasticity and short-term memory. The cells produce interleukin-17, which stimulates the production of brain-derived neurotrophic growth factor. Published in the October 11 Science Immunology, the data imply that regular communication between the immune and central nervous systems bolster everyday brain function.
- A specialized subset of γδ T cells lurks in mouse meninges.
- They bolster synaptic plasticity and short-term memory.
- The mediator is IL-17, which stimulates production of BDNF.
“This manuscript is fascinating on several levels,” wrote Matthias Nahrendorf, Massachusetts General Hospital, Boston, to Alzforum. “That a T cell subset residing in the meninges can affect short-term memory via cytokine secretion is a new concept and an example of how immune resident cells are important for non-immune functions in the steady state,” Nahrendorf wrote. He was not involved in the research.
Ribot and colleagues focused on a particular type of cell called gamma delta (γδ) T cells, named after their heterodimeric T cell receptors. These sentinels stand guard in epithelial and mucosal tissues, where they serve as a first line of defense against viruses, parasites, cancer cells, and other insults. In addition, these cells have been reported to participate in homeostatic and repair processes, for instance enhancing bone restoration and regulating body temperature (Ono et al., 2016; Kohlgruber et al., 2018).
Recent reports catalogue a plethora of immune cells in the healthy mouse brain, including dendritic, T, and B (Jul 2017 news). Could γδ T cells be among them, and might they contribute to brain function?
Co-first authors Miguel Ribeiro and Helena Brigas used flow cytometry to analyze the immune cell complement of the meninges of wild-type mice. The brain’s three protective membranes sport a more diverse array of immune cells than its parenchyma. The researchers found a set of γδ T cells that was present from birth and persisted throughout the lifespan. Half of this population produced small amounts of the non-inflammatory cytokine IL-17. They were present regardless of whether the mice had been exposed to triggers, for example bacteria in the gut or pro-inflammatory cytokines known to drive γδ T cell expansion in brain disorders such as experimental autoimmune encephalitis. This suggests the γδ T cell subtype always resides in the meninges, the authors write.
To see if γδ T cells influence behavior, the researchers tested genetic knockouts lacking either γδ T cells or IL-17. Exploratory behavior, motor skills, and anxiety levels all seemed normal. But mice lacking γδ T cells or IL-17, or mice injected intracerebroventricularly with antibodies to IL-17, were unable to remember which arm of a Y-maze they had just explored, suggesting short-term memory took a hit. When trained for a week in the Morris water maze, a test of longer-term spatial memory, all animals performed normally.
To probe what might possibly explain a selective effect on short-term memory, the scientists analyzed hippocampal slices from the IL-17 knockouts. If the mice had undergone no training just before the hippocampus was excised, long-term potentiation looked normal. Just after a session in the Y-maze, however, long-term potentiation was impaired. LTP was partially restored if slices were preincubated with IL-17. In animals that were trained for a week in the Morris water maze, LTP also appeared normal. Ribot hypothesizes that IL-17 is required to promote LTP only after a short-term memory task, while other mechanisms contribute during long-term tasks.
How might IL-17 boost LTP? Cytokines are known to modulate expression of brain-derived neurotrophic factor (BDNF), which regulates synaptic plasticity (for a review, see Lu et al., 2013). To see if IL-17 worked through BDNF, the authors measured the trophin in the hippocampi of IL-17 knockouts. BDNF levels dropped by 30 percent after training in the Y-maze and, as before, the animals poorly distinguished the novel arm of the maze. Intracerebroventricular injections of BDNF rescued this short-term memory deficit in mice deficient in IL-17 or γδ T cells. Incubating hippocampal slices from IL-17 knockouts with BDNF also restored LTP.
The results suggest that γδ T cells in the meninges might help regulate short-term memory by releasing IL-17, which in turn stimulates production of BDNF from brain cells. The results align with a previous report that meningeal T cell-derived IL-4 supports normal learning and memory in mice (Derecki et al., 2010). Likewise, IL-13 from a different subset of T cells has been found necessary for normal performance in the Morris water maze (Brombacher et al., 2017).
The authors do not know yet which cells produce BDNF in response to IL-17. Microglia, astrocytes, certain neurons, pericytes, and endothelial cells are all candidates. It is also unclear where these T cells are located in the meninges, how they are recruited, or how IL-17 regulates BDNF levels. “Unraveling these connections may improve our understanding of this emerging field of neuroimmunology, and may provide new opportunities for the manipulation of meningeal spaces in order to benefit healthy and diseased brain,” Jonathan Kipnis and Kalil Alves De Lima, University of Virginia, Charlottesville, wrote to Alzforum.
Does this work have implications for neurodegenerative disease? It’s not certain that the same cells affect short-term memory in people, Ribot said. If so, it may become possible to boost IL-17 production to prevent or treat memory loss, she said. “Moving forward, understanding the mechanism underlying the regulation of this subset of T cells could be important for the design of future immunotherapy for neurodegenerative disease,” she said.—Gwyneth Dickey Zakaib
- Ono T, Okamoto K, Nakashima T, Nitta T, Hori S, Iwakura Y, Takayanagi H. IL-17-producing γδ T cells enhance bone regeneration. Nat Commun. 2016 Mar 11;7:10928. PubMed.
- Kohlgruber AC, Gal-Oz ST, LaMarche NM, Shimazaki M, Duquette D, Koay HF, Nguyen HN, Mina AI, Paras T, Tavakkoli A, von Andrian U, Uldrich AP, Godfrey DI, Banks AS, Shay T, Brenner MB, Lynch L. γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis. Nat Immunol. 2018 May;19(5):464-474. Epub 2018 Apr 18 PubMed.
- Lu B, Nagappan G, Guan X, Nathan PJ, Wren P. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci. 2013 Jun;14(6):401-16. PubMed.
- Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med. 2010 May 10;207(5):1067-80. Epub 2010 May 3 PubMed.
- Brombacher TM, Nono JK, De Gouveia KS, Makena N, Darby M, Womersley J, Tamgue O, Brombacher F. IL-13-Mediated Regulation of Learning and Memory. J Immunol. 2017 Apr 1;198(7):2681-2688. Epub 2017 Feb 15 PubMed.
- Kipnis J. Multifaceted interactions between adaptive immunity and the central nervous system. Science. 2016 Aug 19;353(6301):766-71. PubMed.
- Ribeiro M, Brigas HC, Temido-Ferreira M, Pousinha PA, Regen T, Santa C, Coelho JE, Marques-Morgado I, Valente CA, Omenetti S, Stockinger B, Waisman A, Manadas B, Lopes LV, Silva-Santos B, Ribot JC. Meningeal γδ T cell-derived IL-17 controls synaptic plasticity and short-term memory. Sci Immunol. 2019 Oct 11;4(40) PubMed.