BRAIN T CELL SUBSETS POTENTIALLY PARTICIPATE DYNAMICALLY IN NEUROINFLAMMATION AND NEURODEGENERATION

G. Ricciardi¹ and U. Vincenzi²

¹ Director of UOC San Severo Hospital “Masselli Mascia” San Severo, Italy;
² Giovanni Paolo II Health Center, Foggia, Italy.

*Correspondence to:
Giuseppe Ricciardi,
Director of UOC San Severo Hospital “Masselli Mascia”,
San Severo, Italy.
e-mail: peppe.ricciardi@virgilio.it

ABSTRACT

T cells play a crucial role in the immune response by producing soluble mediators, including cytokines. Mature and activated T cells are effector cells and present different phenotypes. T cells have a certain plasticity that allows them to adapt to different antigens. They are distinguished by their different differentiation and production of molecules and intervene both in modulating the immune system and in brain inflammation. T cells are divided into various subsets including T helper cells (Th), cytotoxic T cells (Tc), and regulatory T cells (Treg). Their activation leads to the production of specific transcription factors that regulate the expression of specific genes. CD4+ T cells are helper cells that aid in the production of antibodies, while CD8+ Tc cells are killer cells that act against infected or abnormal cells and mediate neuroinflammation. CD8+ cells mediate neurodegeneration in neuroinflammatory diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Treg cells are immune regulators and regulate inflammation. Dysregulation of T cells mediates many neurological disorders such as depression and schizophrenia. The in-depth study of T cells and their subsets helps to better understand their mechanism of action and their function in neurological diseases.

KEYWORDS: T cell, subset, neuroinflammation, neurodegeneration, immune response

INTRODUCTION

T cells play a crucial role in the immune response and act by producing soluble mediators and by cell-to-cell contact (1). Many T cell subsets have been characterized, and terminally differentiated subtypes are considered effector cells. Data suggests that the phenotype of all existing T cells has not yet been defined (2). T cells can have mixed phenotypes that interconvert from one subset phenotype to another that, through specific signals, can produce molecules with memory. T cells have a certain plasticity to adapt to the immune response and various microenvironments (3). They are particularly important for the defense against pathogens that invade tissues (4). T cell subsets are distinguished by their differentiation and identified by the expressed cell surface markers but can also be classified by the molecules that they produce (5). It is important to understand the markers of T cell subsets, transcriptional regulators, effector molecules, and the function of the subsets in the immune response (6). Understanding these T cell subsets and their regulation can be an important tool in the therapy against immune diseases. T cells and their subsets play an important role in both immune system modulation, neuroinflammation, and neurodegeneration in the brain (7) (Table I).

Table I. Some T-cell subset receptors (surface phenotype).

T cell subsets are part of the adaptive immune system and are classified based on their function and surface markers. Transcription factors are critical in determining T-cell subset differentiation and function (8). T cells are categorized into various subtypes, including T helper cells (Th), cytotoxic T cells (Tc), and regulatory T cells (Treg), amongst others (9). Each subtype’s differentiation is driven by specific transcription factors that regulate the expression of lineage-specific genes (Table II).

Table II. T helper (Th) cell transcription factors.

DISCUSSION

CD4+ cells have various subtypes such as Th1, Th2, Th17, and Treg (10). These cells act through the release of cytokines and are classified based on their function and surface markers.

CD8+ Tc cells are killer cells and act against infected or damaged cells, causing inflammation (11). These cells also act against abnormal neurons, causing neuroinflammation (12). CD8+ T cells can act against myelin and neuronal antigens, causing damage at the axonal level (13).

Tregs are immune T cells that regulate homeostasis and the immune response when it is too high. Tregs may also help maintain brain health and regulate inflammation (14). Treg cells suppress excessive inflammation and, when reduced, contribute to the progression of brain disease. T cells are found in the brain and cerebrospinal fluid in limited numbers due to the blood-brain barrier (BBB) limiting their entry (15). T cell subsets play a dual role in neuroprotection and neuroinflammation. Neuroinflammation is a pathological effect that occurs in many brain diseases including Alzheimer’s disease (AD), multiple sclerosis (MS), and Parkinson’s disease (PD) (16). Activated innate Th1 cells in the brain produce interferon-gamma (IFN-γ), which causes inflammation and neuronal damage, while Th17 cells produce IL-17, a cytokine that participates in the breakdown of the BBB, allowing inflammatory cells to enter the brain (17).

In neurodegenerative diseases such as AD and PD, T cells are found to be infiltrated in brain regions with amyloid plaques (AD) or Lewy bodies (PD) (18). In these diseases, inflammatory cytokines play a fundamental role in neurodegeneration. In addition, dysregulation of T cells and their subsets mediates many psychiatric disorders such as depression and schizophrenia by activating inflammation (15). In fact, T cells enter the brain after BBB breakdown caused by systemic inflammation. Cytokines released into brain tissue alter the physiology of neurons and microglia (19). These effects provide the basis for promising therapeutic advancement that may involve enhancing Treg cells or inhibiting pro-inflammatory cytokines such as IL-1, TNF, IL-6, and IL-17 (20).

Naive T cells are crucial elements of our immune system and participate in the pathophysiology of the brain (21). Naive T cells are T lymphocytes that have not yet encountered their specific antigen which are called “virgin cells” and are ready to be activated by a specific antigen presented by antigen-presenting cells (APCs). These cells originate in the bone marrow, mature in the thymus, and then circulate in the blood and lymph nodes, waiting to be activated (22). Once activated, they differentiate into effector T cells or memory T cells. Naive T cells can affect the brain directly or indirectly through several mechanisms. Naive T cells do not normally cross the BBB, but in the case of neurodegenerative disease where the BBB is dysregulated, T cells can enter the brain (23).

“T cell exhaustion in the brain” refers to the phenomenon in which T cells lose their functional capacity after prolonged activation in response to chronic infections, tumors, or autoimmune conditions (24). Prolonged immune activation leads to T cell exhaustion, a reaction which may be particularly important in the context of neuroinflammatory or neurodegenerative diseases (25). Exhausted T cells have reduced cytokine production, proliferation, and cytotoxicity, impairing their ability to fight infections or tumors.

Anergic T cells in the brain play a role in the immune system’s regulation to maintain balance and prevent excessive inflammation or autoimmunity (26). T cell anergy is a state of functional unresponsiveness in T cells, where they are alive but fail to proliferate or produce cytokines upon stimulation (27). This occurs when T cells receive signal 1 (antigen recognition via the T-cell receptor) without signal 2 (costimulatory signals, e.g., CD28 interaction with B7 molecules on APCs). T cells infiltrating the brain in certain conditions such as neuroinflammation, infection, or autoimmunity, may encounter signals capable of producing immunological tolerance that leads to anergy (28).

Memory T cells are a subset of T lymphocytes that are primarily associated with the immune system (21). There is growing interest in how they might interact with or influence the brain. Memory T cells can cross the BBB under certain conditions, such as during neuroinflammation (29). In diseases such as MS, memory T cells target myelin, leading to neurodegeneration.

Natural Killer T (NKT) cells are a subset of immune cells that bridge the innate and adaptive immune systems (30). They are known for their role in recognizing lipid antigens presented by the CD1d molecule and producing large amounts of cytokines (31). Their relationship to the brain and neurological functions is a growing area of research. NKT cells are primarily studied in the context of the immune system but they are also involved in neuroinflammation and brain homeostasis. NKT cells are known to secrete cytokines such as IFN-γ and IL-4, which influence inflammation (32).

Gamma delta (γδ) T cells are a unique subset of T cells that play a role in immune surveillance and tissue homeostasis, including in the brain (33). Unlike the more common alpha-beta (αβ) T cells, γδ T cells have a distinct T cell receptor (TCR) composed of γ and δ chains. These cells are involved in both innate and adaptive immunity and are notable for their ability to respond to non-peptide antigens without the need for antigen presentation by major histocompatibility complex (MHC) molecules (34). γδ T cells are implicated in neuroinflammatory conditions, such as MS and other autoimmune diseases, and are thought to contribute to the breakdown of the BBB and the recruitment of other inflammatory cells into the central nervous system (CNS) (35).

CD8αα T cells express a homodimer of the CD8α chain, unlike conventional CD8αβ T cells, which express a heterodimer of CD8α and CD8β (36). CD8αα T cells often express TCRs with limited diversity, such as γδ TCRs or invariant αβ TCRs, which are associated with innate-like immune responses. These cells are involved in immune regulation, tissue repair, and maintaining homeostasis, and they are generally less cytotoxic than CD8αβ T cells (37).

CONCLUSIONS

Today we know that T cells can infiltrate the CNS in both physiological and pathological conditions and their presence is tightly regulated by the BBB. Th1 cells release IFN-γ, which activates microglia and astrocytes, exacerbating neuroinflammation, while TH17 cells produce IL-17, which disrupts the BBB, allowing further immune infiltration. T cell subtypes have been implicated in MS, AD, and PD. CD8+ cells can directly target neurons, contributing to neurodegeneration, while Treg cells suppress excessive inflammation. It is interesting to understand which T cell subtypes mediate the pathophysiological state of the brain and their functions.

Modulating T cell responses using immune inhibitors, Treg-based therapies, or cytokine blockade could offer potential treatment strategies for neurodegenerative diseases.

Conflict of interest

The authors declare that they have no conflict of interest.

REFERENCES

1. Smith-Garvin JE, Koretzky GA, Jordan MS. T Cell Activation. Annual Review of Immunology. 2009;27(1):591-619.
2. Whitby L, Whitby A, Fletcher M, Barnett D. Current laboratory practices in flow cytometry for the enumeration of CD 4+T-lymphocyte subsets. Cytometry Part B: Clinical Cytometry. 2015;88(5):305-311. doi:https://doi.org/10.1002/cyto.b.21241
3. Zhu J. T Helper Cell Differentiation, Heterogeneity, and Plasticity. Cold Spring Harbor Perspectives in Biology. 2017;10(10):a030338. doi:https://doi.org/10.1101/cshperspect.a030338
4. MacIver NJ, Michalek RD, Rathmell JC. Metabolic Regulation of T Lymphocytes. Annual Review of Immunology. 2013;31(1):259-283. doi:https://doi.org/10.1146/annurev-immunol-032712-095956
5. Wang S, Zhong N, Zhang X, et al. OMIP 071: A 31‐Parameter Flow Cytometry Panel for In‐Depth Immunophenotyping of Human T‐Cell Subsets Using Surface Markers. Cytometry Part A. 2020;99(3):273-277. doi:https://doi.org/10.1002/cyto.a.24272
6. Mueller SN, Gebhardt T, Carbone FR, Heath WR. Memory T Cell Subsets, Migration Patterns, and Tissue Residence. Annual Review of Immunology. 2013;31(1):137-161. doi:https://doi.org/10.1146/annurev-immunol-032712-095954
7. DeMaio A, Mehrotra S, Sambamurti K, Husain S. The role of the adaptive immune system and T cell dysfunction in neurodegenerative diseases. Journal of Neuroinflammation. 2022;19(1). doi:https://doi.org/10.1186/s12974-022-02605-9
8. Vignali DAA, Collison LW, Workman CJ. How regulatory T cells work. Nature Reviews Immunology. 2008;8(7):523-532. doi:https://doi.org/10.1038/nri2343
9. Zhao MQ, Wang LH, Lian GW, et al. Characterization of lymphocyte subsets in peripheral blood cells of children with EV71 infection. Journal of Microbiology, Immunology and Infection. 2020;53(5):705-714. doi:https://doi.org/10.1016/j.jmii.2019.03.001
10. Luckheeram RV, Zhou R, Verma AD, Xia B. CD4+T Cells: Differentiation and Functions. Clinical and Developmental Immunology. 2012;2012(925135):1-12. doi:https://doi.org/10.1155/2012/925135
11. Uzhachenko RV, Shanker A. CD8+ T Lymphocyte and NK Cell Network: Circuitry in the Cytotoxic Domain of Immunity. Frontiers in Immunology. 2019;10. doi:https://doi.org/10.3389/fimmu.2019.01906
12. Chevalier G, Suberbielle E, Monnet C, et al. Neurons are MHC Class I-Dependent Targets for CD8 T Cells upon Neurotropic Viral Infection. PLOS Pathogens. 2011;7(11):e1002393-e1002393. doi:https://doi.org/10.1371/journal.ppat.1002393
13. Van Kaer L, Postoak JL, Wang C, Yang G, Wu L. Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE. Cellular & Molecular Immunology. 2019;16(6):531-539. doi:https://doi.org/10.1038/s41423-019-0221-5
14. Mehdi Benamar, Chen Q, Martinez-Blanco M, Chatila TA. Regulatory T cells in allergic inflammation. Seminars in immunology. 2023;70:101847-101847. doi:https://doi.org/10.1016/j.smim.2023.101847
15. Piehl N, van Olst L, Ramakrishnan A, et al. Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. Cell. 2022;185(26):5028-5039.e13. doi:https://doi.org/10.1016/j.cell.2022.11.019
16. Yoshimura A, Ohyagi M, Ito M. T cells in the brain inflammation. Advances in Immunology. 2023;157:29-58. doi:https://doi.org/10.1016/bs.ai.2022.10.001
17. McQuillan K, Lynch MA, Mills KHG. Activation of mixed glia by Aβ-specific Th1 and Th17 cells and its regulation by Th2 cells. Brain, Behavior, and Immunity. 2010;24(4):598-607. doi:https://doi.org/10.1016/j.bbi.2010.01.003
18. Bassil F, Brown HJ, Pattabhiraman S, et al. Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ Pathology. Neuron. 2020;105(2):260-275.e6. doi:https://doi.org/10.1016/j.neuron.2019.10.010
19. Velasco‐Estevez M, Rolle SO, Mampay M, Dev KK, Sheridan GK. Piezo1 regulates calcium oscillations and cytokine release from astrocytes. Glia. 2019;68(1):145-160. doi:https://doi.org/10.1002/glia.23709
20. Levite M. Glutamate, T cells and multiple sclerosis. Journal of Neural Transmission. 2017;124(7):775-798. doi:https://doi.org/10.1007/s00702-016-1661-z
21. K. Ayasoufi, Wolf DM, S.L. Namen, et al. Brain resident memory T cells rapidly expand and initiate neuroinflammatory responses following CNS viral infection. Brain, behavior, and immunity. 2023;112:51-76. doi:https://doi.org/10.1016/j.bbi.2023.05.009
22. Chongsathidkiet P, Jackson C, Koyama S, et al. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nature Medicine. 2018;24(9):1459-1468. doi:https://doi.org/10.1038/s41591-018-0135-2
23. Wiatr M, Stump-Guthier C, Latorre D, et al. Distinct migratory pattern of naive and effector T cells through the blood–CSF barrier following Echovirus 30 infection. Journal of Neuroinflammation. 2019;16(1). doi:https://doi.org/10.1186/s12974-019-1626-x
24. Beltra JC, Manne S, Abdel-Hakeem MS, et al. Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms. Immunity. 2020;52(5):825-841.e8. doi:https://doi.org/10.1016/j.immuni.2020.04.014
25. Shir Zaccai, Nemirovsky A, Lerner L, et al. CD4 T-cell aging exacerbates neuroinflammation in a late-onset mouse model of amyotrophic lateral sclerosis. Journal of Neuroinflammation. 2024;21(1). doi:https://doi.org/10.1186/s12974-023-03007-1
26. Schwartz RH. T cell Anergy. Annual Review of Immunology. 2003;21:305-334. doi:https://doi.org/10.1146/annurev.immunol.21.120601.141110
27. Schwartz RH. T cell clonal anergy. Current Opinion in Immunology. 1997;9(3):351-357. doi:https://doi.org/10.1016/s0952-7915(97)80081-7
28. Appleman LJ, Boussiotis VA. T cell anergy and costimulation. Immunological Reviews. 2003;192(1):161-180. doi:https://doi.org/10.1034/j.1600-065x.2003.00009.x
29. Ford RK, Juillard P, Hawke S, Grau GE, Marsh-Wakefield F. Cladribine Reduces Trans-Endothelial Migration of Memory T Cells across an In Vitro Blood–Brain Barrier. Journal of Clinical Medicine. 2022;11(20):6006. doi:https://doi.org/10.3390/jcm11206006
30. Li Z, Li M, Shi SX, et al. Brain transforms natural killer cells that exacerbate brain edema after intracerebral hemorrhage. The Journal of Experimental Medicine. 2020;217(12). doi:https://doi.org/10.1084/jem.20200213
31. Kanellopoulos J. Natural killer T cells. Biomedical Journal. 2015;38(6):469-469. doi:https://doi.org/10.1016/j.bj.2016.01.007
32. Ni SJ, Qiu YH, Lu JH, Cao BB, Peng YP. Effect of cerebellar fastigial nuclear lesions on differentiation and function of thymocytes. Journal of Neuroimmunology. 2010;222(1-2):40-47. doi:https://doi.org/10.1016/j.jneuroim.2010.02.017
33. Lewis EL, Tulina N, Anton L, Brown AG, Porrett PM, Elovitz MA. IFNγ-Producing γ/δ T Cells Accumulate in the Fetal Brain Following Intrauterine Inflammation. Frontiers in Immunology. 2021;12. doi:https://doi.org/10.3389/fimmu.2021.741518
34. Sun H, Sun C, Xiao W, Sun R. Tissue-resident lymphocytes: from adaptive to innate immunity. Cellular & Molecular Immunology. 2019;16(3):205-215. doi:https://doi.org/10.1038/s41423-018-0192-y
35. Wo J, Zhang F, Li Z, Sun C, Zhang W, Sun G. The Role of Gamma-Delta T Cells in Diseases of the Central Nervous System. Frontiers in Immunology. 2020;11. doi:https://doi.org/10.3389/fimmu.2020.580304
36. Park JE, Botting RA, Domínguez Conde C, et al. A cell atlas of human thymic development defines T cell repertoire formation. Science. 2020;367(6480):eaay3224. doi:https://doi.org/10.1126/science.aay3224
37. Su X, Gao Y, Yang R. Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis. Cells. 2022;11(15):2296. doi:https://doi.org/10.3390/cells11152296