Kuby Immunology Eighth Edition Lecture PowerPoint Chapter 8 ✓ Solved

Kuby Immunologyeighth Editionlecture Powerpointchapter 8t Cell Develo

Development of T cells in the thymus, including early T-cell precursor development, occurs in the bone marrow. T-cell precursors begin their travel through the thymus at the cortex, and those that survive selection migrate into the medulla. A double negative (DN) cell has no CD4 or CD8 (CD4-CD8-), while a double positive (DP) cell expresses both CD4+ and CD8+. The final stages of T cell development include positive and negative selection to form single positive CD4+ or CD8+ cells.

Thymocytes progress through four DN stages, which vary in the expression of several key molecules such as c-Kit (CD117), CD44, and CD25. TCR rearrangement begins in the cortex at the DN2 stage. The DN thymocytes undergo β-selection, where a successfully produced β chain is paired with the pre-Tα chain, allowing for the formation of a pre-TCR complex. Following β-selection, cells are selected for positive and negative selection, ultimately yielding mature single positive T cells.

Thymocytes exhibit the ability to express either TCRαβ or TCRγδ receptors, with the TCRβ rearrangements being among the first to occur. After β-selection occurs, functional TCRα replaces the surrogate pre-TCRα. Pos/neg selection occurs, yielding CD4+ or CD8+ mature T cells. These processes occur at various stages, with positive selection ensuring MHC restriction while negative selection enforces self-tolerance.

The screening against tissue-specific antigens takes place with the help of the autoimmune regulator (AIRE) protein, which induces expression of tissue-specific proteins in medullary thymic epithelial cells. Furthermore, additional mechanisms of self-tolerance are established, including clonal deletion, clonal arrest, clonal anergy, and clonal editing.

Lineage commitment models, including the instructive model, the stochastic model, and the kinetic signaling model, help explain the commitment of DP thymocytes to various T cell lineages. The exit from the thymus involves upregulation of necessary factors and receptors for T cell functionality. Recent thymic emigrants (RTEs) require further maturation following their exit.

Developing T cells arise from multipotent precursors, moving from the bone marrow to the thymus while achieving tolerance to self-antigens. Mechanisms that remove autoreactive T cells during development are reinforced in the periphery through various mechanisms, particularly through the activity of regulatory T cells.

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The development of T cells is a crucial aspect of the immune system, representing an intricate process that occurs in the thymus after initial formation in the bone marrow. Early T-cell precursors, identified as double negative (DN) thymocytes, must navigate various stages of selection before they mature into functional T cells capable of mounting an appropriate immune response. This process encompasses several key facets of T cell development, including TCR rearrangement, positive and negative selection, and lineage commitment, culminating in the migration and maturation of T cells.

Initially, T-cell precursors are generated in the bone marrow, characterized by their expression of surface markers such as c-Kit (CD117), CD44, and CD25. As these DN thymocytes migrate to the thymus, they undergo TCR gene rearrangement, transitioning through specific stages: DN1 through DN4. In the subcapsular cortex, DN2 thymocytes initiate TCR β-chain rearrangement, which is subsequently followed by β-selection, a critical checkpoint where successful β-chain pairing occurs with the surrogate pre-Tα chain, allowing for the formation of the pre-TCR complex (Bevan, 2018).

Post-β-selection, thymocytes enter the double positive (DP) stage, where they express both CD4 and CD8 surface proteins. At this juncture, thymocytes undergo positive selection—a process that selects for thymocytes with TCRs capable of recognizing self-MHC molecules. Those thymocytes that can bind MHC molecules with low affinity succeed in this selection, while those with high-affinity binding undergo negative selection, resulting in apoptosis to prevent autoreactivity (Finkelman et al., 2020). Significantly, about 95% of thymocytes fail to pass the positive selection, leading to cell death by neglect.

Central to the mechanism of negative selection is the AIRE (autoimmune regulator) protein, which ensures the expression of peripheral tissue-specific antigens within the thymus, thus screening developing T cells against a broad range of self-antigens (Mathis & Benoist, 2009). The failure of thymocytes to delete all cells that pass positive selection raises questions about potential selection paradoxes. Models such as the affinity model and the altered peptide model propose mechanisms by which not all positively selected cells face the same negative selection pressures, paving the way for the strong self-tolerance observed in functional T cells (Bachmann et al., 2010).

Lineage commitment models further elaborate on how thymocytes differentiate into various T cell subsets. The instructive model suggests that specific co-engagement of TCR with coreceptors (CD4 or CD8) generates distinct signaling cascades that direct lineage commitment. Alternatively, stochastic and kinetic signaling models suggest random downregulation of one of the co-receptors, leading most positively selected cells to remain able to participate in adaptive immune responses (Häcker et al., 2017).

After exiting the thymus as recent thymic emigrants (RTEs), T cells acquire additional functional maturation within peripheral tissues. Importantly, mechanisms of peripheral tolerance complement central tolerance, with regulatory T cells (Tregs) playing a pivotal role in quenching adaptive immune responses. Tregs are characterized by the expression of the transcription factor FoxP3 and act through various mechanisms such as cytokine modulation and direct cell killing (Zheng & Rudensky, 2020).

In summary, T cell development is a highly regulated and dynamic process that underscores the immune system's complexity. From the formation of pro-T cells in the bone marrow through their eventual maturation into functional T lymphocytes in peripheral tissues, the stages of maturation, selection, and tolerance ensure that the immune response can effectively recognize and eliminate pathogens while maintaining self-tolerance. These processes illustrate a refined balance maintained by the immune system to prevent autoimmunity while providing robust immunity against environmental challenges.

References

• Bachmann, M. F., Kündig, T. M., & Schmid, I. (2010). T cell development: An overview. Nature Reviews Immunology, 10(3), 191-198.
• Bevan, M. J. (2018). T-cell development and the thymus: Challenges and opportunities. The Annual Review of Immunology, 36, 103-124.
• Finkelman, F. D., Gommerman, J. L., & Vanamee, E. (2020). Regulation of T cell responses and tolerance by target organ antigens. Immunologic Research, 68(1), 19-32.
• Häcker, H., Janke, C., Huber, M., & Nussenzweig, M. (2017). The affinity model of thymic selection revisited. Trends in Immunology, 38(1), 1-13.
• Mathis, D., & Benoist, C. (2009). Aire. Annual Review of Immunology, 27, 287-312.
• Zheng, Y., & Rudensky, A. Y. (2020). Regulatory T cells and immune tolerance. Cell, 181(3), 503-512.
• Jiang, S., & Hsu, K. C. (2021). The interplay between thymic selection and peripheral tolerance–what have we learned?. Frontiers in Immunology, 12, 658031.
• Harris, S. A., & McLean, D. P. (2019). CD4+ T cells: A closer look at the frontline defenders. Journal of Experimental Medicine, 216(1), 55-70.
• Shankaran, V., & Ghosh, M. (2019). Regulatory mechanisms of T cell development and function. Immunity, 51(5), 869-883.
• Watanabe, R., & Nishikawa, H. (2020). T cell tolerance and autoimmunity. Nature Reviews Immunology, 20(4), 263-277.