T Cell Diversity in the Human CNS: Insights into Immune Surveillance and Neuroinflammation

Immune surveillance within the central nervous system (CNS) plays a crucial role in maintaining the delicate balance between protecting against pathogens and avoiding neuroinflammatory damage. T cells are key players in this surveillance, particularly within the cerebrospinal fluid (CSF), which is the primary route for their entry into the CNS. Recent advances in single-cell sequencing have allowed for an unprecedented exploration of the diversity, function, and adaptation of these immune cells in both healthy individuals and patients with neuroinflammatory diseases like multiple sclerosis (MS). The research led by Jenna L. Pappalardo and colleagues sheds light on the dynamic transcriptomic and clonal landscapes of T cells in the CNS and their implications for immune regulation in health and disease​.

T Cells in the CSF:
A Vital Gateway to the CNS T cells in the CNS provide necessary immune surveillance to fend off potential pathogens while maintaining CNS integrity. The CSF is rich in T cells, with integrin α4β1 and the chemokine receptor CXCR3 being essential for T cell migration into the CNS​. In this study, Pappalardo et al. characterized the transcriptomic profiles of T cells from the blood and CSF of healthy individuals using single-cell RNA sequencing (scRNA-seq). They discovered distinct clusters of naïve and memory T cells within these compartments, with the CSF predominantly composed of memory T cells​. This distinction highlights the tissue-specific adaptation of T cells as they transition from the blood to the CNS, a process necessary for effective immune surveillance.

Phenotypic Diversity of T Cells in the CNS:
The study identified distinct phenotypic states of T cells in the blood and CSF, focusing on memory CD4 and CD8 T cell populations. These cells exhibited different profiles depending on their location. Memory T cells in the CSF were enriched with genes related to tissue residency and cytotoxicity, pointing to their functional adaptation to the CNS environment​. Among the notable findings was the characterization of specific clusters of CD4 memory T cells (CSF.2 and CSF.3) that expressed high levels of TH1-associated genes, while CSF.3 also exhibited cytotoxic genes such as granzyme A (GZMA) and granzyme K (GZMK)​. This suggests that even in a non-inflammatory state, T cells in the CSF are poised for rapid cytotoxic responses, potentially providing a first line of defense against CNS infections.

Clonal Expansion and T Cell Adaptation: Clonal expansion is a hallmark of T cells that have encountered their antigen and undergone proliferation. The study analyzed clonal T cell populations shared between the blood and CSF, revealing greater transcriptional divergence in T cells residing in different tissues​. Clonal expansion in the CSF was predominantly observed in CD8 memory T cells, which expressed high levels of cytotoxicity-related genes. These clonally expanded cells also displayed features of tissue-resident memory T cells (TRM), including markers like CD69 and CXCR6, indicating their adaptation to the CNS environment​.

Implications for Multiple Sclerosis (MS):
In MS, autoreactive T cells are believed to play a key role in driving neuroinflammation. Pappalardo et al. compared T cell profiles in healthy individuals and patients with newly diagnosed relapsing-remitting MS​. While overall T cell composition did not differ significantly between the groups, there were important functional differences. T cells in the CSF of MS patients showed heightened expression of genes related to activation and cytotoxicity, such as CD69 and interferon-gamma (IFNG), suggesting a more activated state​. Moreover, clonally expanded T cells in MS CSF exhibited elevated expression of cytotoxic and effector-related genes compared to healthy controls, highlighting their potential involvement in driving the autoimmune response.

T Cells and Neuronal Interactions:
One of the fascinating aspects of this study was the investigation into potential interactions between T cells and neurons or glial cells in the CNS. By analyzing brain parenchymal cells from post-mortem and epilepsy surgery tissues, the researchers identified communication pathways between T cells and CNS-resident cells​. T cells expressed genes involved in effector functions, including IFNG and tumor necrosis factor (TNF), which could influence the function of neurons and glial cells​. This finding opens up new avenues for understanding how immune cells modulate CNS homeostasis and contribute to neuroinflammatory diseases.

Concluding Remarks:
The transcriptomic and clonal characterization of T cells in the human CNS provided by Pappalardo et al. offers critical insights into the role of T cells in both immune surveillance and neuroinflammation. In healthy individuals, CSF T cells exhibit a unique cytotoxic phenotype poised for rapid response, while in MS, these cells show enhanced activation and effector functions, likely contributing to disease pathology. This study underscores the importance of understanding the tissue-specific adaptations of immune cells and their potential implications for neuroimmune diseases like MS​.

References:
Pappalardo, J. L., Zhang, L., Pecsok, M. K., Perlman, K., Zografou, C., Raddassi, K., ... & Hafler, D. A. (2020). Transcriptomic and clonal characterization of T cells in the human central nervous system. Science immunology, 5(51), eabb8786.