Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition
Open accessAbstract
The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69 + CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems. Video Abstract
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There is high concordance between genes upregulated in 'digested' PBMCs and those upregulated in tissue-resident cells following tissue digestion in the Pasciuto et al. and Crinier et al. studies.
“We also found a high concordance between genes that were upregulated in ‘digested’ PBMCs and those that were observed as upregulated in tissue-resident cells following tissue digestion in the Pasciuto et al.42 and Crinier et al.46 studies (Supplementary Fig. 13f).”
From Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain (2022) · cites this paper as Pasciuto et al.42
The STAR★Methods (Method Details; page unavailable) describe digestion of brain tissue to prepare single-cell suspensions, and the Results report differentially expressed genes in isolated microglia. The copy does not show that those genes were upregulated because of digestion, or compare digested with undigested tissue. The claimed high concordance is the citing authors’ own finding, not a result attributed to Pasciuto et al. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn case-control frameworks, reanalysis of two examples from the literature demonstrates that without knowledge of the exAM signature, it can result in spurious identification of the exAM signature as differentially expressed.
“Second, in case–control frameworks, we demonstrate with our reanalysis of two examples from the literature that, without knowledge of the presence of the exAM signature, it can result in spurious identification of the exAM signature as differentially expressed (Supplementary Note 4)41,42,69,70.”
From Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain (2022) · cites this paper as [42]
Neuronal development is supported and shaped by maternal microbiota.
“In this period, neuronal development takes place (73) and it is supported and shaped by maternal microbiota (74–79).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [78]
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- Authors
- Pasciuto, E., Burton, O. T., Roca, C. P., Lagou, V., Rajan, W. D., Theys, T., Mancuso, R., Tito, R. Y., Kouser, L., Callaerts-Vegh, Z., de la Fuente, A. G., Prezzemolo, T., Mascali, L. G., Brajic, A., Whyte, C. E., Yshii, L., Martinez-Muriana, A., Naughton, M., Young, A., Moudra, A., Lemaitre, P., Poovathingal, S., Raes, J., De Strooper, B., Fitzgerald, D. C., Dooley, J., & Liston, A.
- Affiliations
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Babraham Institute (GB)
- Universitair Ziekenhuis Leuven (BE)
- VIB-KU Leuven Center for Microbiology (BE)
- Queen's University Belfast (GB)
- Corresponding author
- Liston, Adrian
- ORCID
- Pasciuto, Emanuela
- Burton, Oliver T.
- Roca, Carlos P.
- Lagou, Vasiliki
- Theys, Tom
- Mancuso, Renzo
- Tito, Raul Y.
- Kouser, Lubna
- Callaerts-Vegh, Zsuzsanna
- Brajic, Aleksandra
- Whyte, Carly E.
- Yshii, Lidia
- Naughton, Michelle
- Moudra, Alena
- Lemaitre, Pierre
- Poovathingal, Suresh
- Raes, Jeroen
- De Strooper, Bart
- Fitzgerald, Denise C.
- Dooley, James
- Liston, Adrian
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 182
- Issue
- 3
- Pages
- 625-640.e24
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7427333
- OpenAlex
- W3044240100
- Cited by
- 368
- References
- 110
- Citations by year
- 2026: 53 · 2025: 58 · 2024: 66 · 2023: 53 · 2022: 75 · 2021: 55 · 2020: 8
- FWCI
- 18.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lirias (submittedVersion, other-oa)
- Research Portal (Queen's University Belfast) (submittedVersion, cc-by-nc-nd)
- Funders
- Alzheimer's Association
- European Research Council
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia, CD4+ T cells, fetal to adult transition, microglial maturation, CD69, autoantigens, synaptic development, brain development, neuroimmune interactions
- MeSH terms
- Behavior Rating Scale, CD69 Antigens, Adult, Animals, Antigens, Differentiation, T-Lymphocyte, Blood Cells, Brain, Child, Female, Fetus, Humans, Lung, Male, Mice, Inbred C57BL, Middle Aged, Parabiosis, Spleen, Synapses, CD4-Positive T-Lymphocytes, Antigens, CD, Microglia, Pyramidal Cells, Mice, Knockout, Lectins, C-Type, Mice, Neurogenesis, Single-Cell Analysis, Transcriptome
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