Conventional T cells
T cells are a type of white blood cell that protect the body from infection and disease. Two key types, CD4⁺ and CD8⁺ T cells, help connect the gut, immune system and brain.
In the gut, T cells interact closely with bacteria that live in our intestines. These microbes influence how T cells develop and respond. CD4⁺ T cells coordinate immune responses by releasing signalling molecules, while CD8⁺ T cells directly destroy infected or damaged cells.
When gut bacteria are imbalanced, T cells can become overactive and release inflammatory signals into the bloodstream. These signals may affect the brain and disrupt the blood–brain barrier, which normally protects it. In some conditions, such as multiple sclerosis, activated T cells can enter the brain and contribute to inflammation.
Understanding how CD4⁺ and CD8⁺ T cells behave helps researchers explore how gut health influences brain function and neurological disease.
Expert information on conventional T cells
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CD4⁺ and CD8⁺ T cells are key mediators within the gut–brain–immune axis, integrating microbiota-derived signals with systemic and central nervous system (CNS) immune responses. Both subsets are shaped by microbial antigens, metabolites and tissue-specific antigen presentation within the intestinal mucosa. Lamina propria dendritic cells condition naïve CD4⁺ T cells toward Th1 and Th17 phenotypes under inflammatory or dysbiotic states via IL-12, IL-6 and IL-23 signalling1. Intestinal CD8⁺ T cells comprise circulating effectors and tissue-resident memory populations influenced by antigen persistence, type I interferons and microbiota composition2.
Experimentally, gut T cells are commonly studied in mice using lamina propria isolation followed by flow or mass cytometry to define effector phenotypes3. Cytokine production is assessed after ex vivo stimulation, while single-cell RNA sequencing enables high-resolution profiling of T cell states across inflammatory conditions. Public datasets from murine and human intestinal immune atlases are accessible via resources such as the Human Cell Atlas4, e.g. see here: https://www.gutcellatlas.org/
Trafficking within the GIBA framework is typically investigated using adoptive transfer of labelled or congenically marked CD4⁺ or CD8⁺ T cells to track migration from gut-associated lymphoid tissue to systemic compartments, including the CNS. Parabiosis models distinguish circulating versus tissue-resident populations, while chemokine receptor profiling (e.g., CCR6, CXCR3) provides insight into migratory potential5.
In neuroinflammatory models, CNS-infiltrating T cells are quantified by flow cytometry or spatially resolved using immunohistochemistry and multiplex imaging. Intravital two-photon microscopy enables dynamic visualisation of T cell behaviour at barrier interfaces, although this remains technically demanding6. Blood–brain barrier integrity can be assessed using tracer permeability assays or contrast-enhanced MRI, providing functional context for immune cell infiltration7.
In humans, peripheral blood profiling by flow cytometry, CyTOF or single-cell transcriptomics is widely used but does not confirm gut origin. T cell receptor sequencing can identify clonal overlap between gut and CNS compartments8. In vitro systems, such as T cell-dendritic cell co-cultures and intestinal organoids, model gut-driven polarisation but incompletely capture systemic trafficking9.
Limitations include variability in murine microbiota, lack of paired human gut–brain datasets, and the need to integrate imaging with molecular profiling10. Multimodal approaches combining immune phenotyping, transcriptomics and imaging are therefore essential to define how gut-conditioned T cells influence CNS immunity.
Text by Doreen Lau, Brunel University of London, Department of Biosciences, Centre for Inflammation Research and Translational Medicine
References
- Honda, K. & Littman, D. R. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75–84 (2016).
- Cheng, L. & Becattini, S. Intestinal CD8+ tissue-resident memory T cells: From generation to function. Eur. J. Immunol. 52, 1547–1560 (2022).
- Shanmugavadivu, A., Carter, K., Zonouzi, A. P., Waisman, A. & Regen, T. Protocol for the collection and analysis of the different immune cell subsets in the murine intestinal lamina propria. STAR Protoc. 5, 103154 (2024).
- Elmentaite, R. et al. Cells of the human intestinal tract mapped across space and time. Nature 597, 250–255 (2021).
- Wang, H., Gavil, N. V., Koewler, N., Masopust, D. & Jameson, S. C. Parabiosis in Mice to Study Tissue Residency of Immune Cells. Curr. Protoc. 2, e446 (2022).
- Bauer, I. J. et al. Visualizing the activation of encephalitogenic T cells in the ileal lamina propria by in vivo two-photon imaging. Proceedings of the National Academy of Sciences 120, (2023).
- Guglielmetti, C. et al. Longitudinal Imaging of T Cells and Inflammatory Demyelination in a Preclinical Model of Multiple Sclerosis Using 18F-FAraG PET and MRI. Journal of Nuclear Medicine 63, 140–146 (2022).
- Kadowaki, A., Saga, R., Lin, Y., Sato, W. & Yamamura, T. Gut microbiota-dependent CCR9+CD4+ T cells are altered in secondary progressive multiple sclerosis. Brain 142, 916–931 (2019).
- Harter, M. F., Recaldin, T. & Gjorevski, N. Organoids as models of immune-organ interaction. Cell Rep. 44, 116214 (2025).
- Mayer, E. A., Tillisch, K. & Gupta, A. Gut/brain axis and the microbiota. Journal of Clinical Investigation 125, 926–938 (2015).
