Morphological Changes in T Cells

T cells, also known as T lymphocytes, are central components of the adaptive immune system. They undergo morphological changes as they transition from a resting state to activation and eventually exhaustion. These changes are critical for optimal T cell receptor signalling and effective antigen recognition. This is typically influenced by interaction with antigen-presenting cells (APCs) and the accumulation of filamentous actin (F-actin) (Smith, 2023).

As a key player in cell-mediated immunity, T lymphocytes remain quiescent for most of their lifespan, transitioning to a proliferative state upon stimulation. Resting T cells are typically spherical or slightly ellipsoidal, with minimal protrusion and highly compacted chromatin structure (Johnson & Thompson, 2022).

Upon activation, T cells undergo significant morphological changes. They transform from a spherical shape to more elongated or flattened forms with increased cell volume. This change is driven by the accumulation of F-actin at the immunological synapse (IS) which is essential for T-cell signaling and interaction with APCs (Chen & Zhang, 2018). F-actin as the microfilaments within the cytoplasm of T cells is crucial for T-cell migration, whereas it helps facilitate the formation of lamellipodia at the leading edge of the cell to further push the cell forward during the movement. As the F-actin accumulates, the T-cell receptors and adhesion molecules are also organized at the contact site with APCs.The increased microvilli density in the cell membrane leads to the cells' expansion in volume that facilitates cell-cell interaction (Brown & Davis, 2019).

The morphological changes of T cells are strongly correlated with the calcium (Ca2+) response; a strong Ca2+ response typically results in a round-flattened shape indicating a effective activation, whereas a weaker response may lead to an elongated-flattened shape (Brown & Davis, 2019).

Exhausted T cells often display a more compact shape and reduced motility due to epigenetic modifications and metabolic shifts. They exhibit reduced glycolysis and an increased reliance on fatty acid oxidation (FAO) for energy, potentially affecting their cellular structure and size (Williams & Lee, 2020). Additionally, they express high levels of inhibitory receptors such as PD-1, LAG-3, and TIM-3, which dampen their effector functions (Johnson & Thompson, 2022). Exhaustion is a progressive state, leading to a hierarchical loss of T cell functions, including cytokine production and cytolytic activity.

Understanding these dynamics is critical for developing strategies to maintain T cell functionality. One approach is to create environments that mimic natural activation platforms, but with more nuanced and sustained stimulation. This can help prevent over-exhaustion by guiding T cells through a gradual activation process, similar to marathon training. Such strategies aim to preserve T-cell potency while minimising the risk of exhaustion.

Can exhausted T cells ever regain their full potential? Or are there ways to prevent exhaustion in the first place? Stay tuned for our next article.

Chloe Chan: Write-up

Kiki Choi: Graphics

Reference list:

Brown, T. A., & Davis, M. M. (2019). Activation effects on the physical characteristics of T lymphocytes. Frontiers in Bioengineering and Biotechnology, 7, Article 338. https://doi.org/10.3389/fbioe.2019.00338

Chen, L., & Zhang, Y. (2018). F-Actin Accumulation and T Cell Activation. Journal of Biological Chemistry, 293(14), 5315-5325. https://doi.org/10.1074/jbc.RA117.001254

Johnson, K. L., & Thompson, R. J. (2022). Fundamentals to therapeutics: Epigenetic modulation of CD8+ T cell exhaustion in the tumor microenvironment. Nature Immunology, 23(5), 631-638. https://doi.org/10.1038/s41590-022-01234-5

Smith, J. (2023). Morphological change of CD4+ T cell during contact with DC modulates T-cell activation by accumulation of F-actin in the immunology synapse. Journal of Immunology, 210(1), 1-10. https://doi.org/10.4049/jimmunol.2200706

Smith, J. M. (2023). T Cell Activation and Morphology. Journal of Immunology, 191(1), 1-10. https://doi.org/10.4049/jimmunol.2200706

Williams, D. R., & Lee, S. J. (2020). Exhausted T cells hijacking the cancer-immunity cycle: Assets and liabilities. Frontiers in Immunology, 11, Article 575. https://doi.org/10.3389/fimmu.2020.00575