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Review
. 2021 Feb;43(1):119-134.
doi: 10.1007/s00281-021-00840-5. Epub 2021 Feb 19.

Dynamics of thymus function and T cell receptor repertoire breadth in health and disease

David Granadier #  1   2   3   4 , Lorenzo Iovino #  1   2 , Sinéad Kinsella #  1   2 , Jarrod A Dudakov  5   6   7
Affiliations
Review

Dynamics of thymus function and T cell receptor repertoire breadth in health and disease

David Granadier et al. Semin Immunopathol. 2021 Feb.

Abstract

T cell recognition of unknown antigens relies on the tremendous diversity of the T cell receptor (TCR) repertoire; generation of which can only occur in the thymus. TCR repertoire breadth is thus critical for not only coordinating the adaptive response against pathogens but also for mounting a response against malignancies. However, thymic function is exquisitely sensitive to negative stimuli, which can come in the form of acute insult, such as that caused by stress, infection, or common cancer therapies; or chronic damage such as the progressive decline in thymic function with age. Whether it be prolonged T cell deficiency after hematopoietic cell transplantation (HCT) or constriction in the breadth of the peripheral TCR repertoire with age; these insults result in poor adaptive immune responses. In this review, we will discuss the importance of thymic function for generation of the TCR repertoire and how acute and chronic thymic damage influences immune health. We will also discuss methods that are used to measure thymic function in patients and strategies that have been developed to boost thymic function.

Keywords: Damage and regeneration; TCR repertoire; Thymus.

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Figures

Fig. 1
Fig. 1
Damage and regeneration in the thymus and TCR repertoire. Steady-state T cell development in the thymus of young, healthy individuals results in the generation of a broad but self-tolerant T cell receptor (TCR) repertoire. It is this diversity of the TCR repertoire that allows for T cell recognition of unknown antigens. However, thymic function progressively declines from puberty resulting in reduced export of newly generated naïve T cells that, coupled with the expansion of existing naïve and memory T cells, leads to a constriction in the diversity of the peripheral TCR repertoire and reduced responsiveness to new antigens. Furthermore, even though the thymus has a remarkable capacity for repair after acute insults, and there is likely continual thymic involution and regeneration in response to stress and infection in otherwise healthy people, acute and profound thymic damage such as that caused by common cancer cytoreductive therapies or the conditioning regimes required for HCT, leads to prolonged T cell deficiency. In the setting of HCT, a well-established therapy with curative potential for a variety of malignant and nonmalignant diseases, delayed T cell reconstitution is an important contributor to transplant-related morbidity and mortality due to infections and malignant relapse. Elements of the figure were generated using Biorender.com
Fig. 2
Fig. 2
Acute injury and endogenous mechanisms of regeneration. (Top) Acute thymus injurious events including acute infection, rises in glucocorticoids and sex hormones, and cytoreductive treatment for HCT or chemotherapy for cancer treatment. (Bottom) Endogenous cell signaling pathways leading to regeneration from acute injury: IL-23 from thymus dendritic cells stimulate the release of IL-22 from innate lymphoid cells (ILCs). ILCs also release RANKL independent of IL-23. IL-22, RANKL, BMP4 (from thymic endothelial cells), and KGF (from thymic fibroblasts) act on thymic epithelial cells (TECs) stimulating their proliferation. TECs release IL-7 required for thymocyte repopulation. Thymocytes produce Vascular Endothelial growth factor which signals to thymic endothelial cells. Bolded arrows indicate endogenous factors that, when given exogenously, have regernative potential. Elements of the figure were generated using Biorender.com
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References

    1. Huda MN, et al. Infant cortisol stress-response is associated with thymic function and vaccine response. Stress. 2019;22:36–43. doi: 10.1080/10253890.2018.1484445. - DOI - PMC - PubMed
    1. Ashwell JD, Lu FW, Vacchio MS. Glucocorticoids in T cell development and function*. Annu Rev Immunol. 2000;18:309–345. doi: 10.1146/annurev.immunol.18.1.309. - DOI - PubMed
    1. Purton JF, et al. Expression of the glucocorticoid receptor from the 1A promoter correlates with T lymphocyte sensitivity to glucocorticoid-induced cell death. J Immunol. 2004;173:3816–3824. doi: 10.4049/jimmunol.173.6.3816. - DOI - PubMed
    1. Dumont-Lagace M, St-Pierre C, Perreault C. Sex hormones have pervasive effects on thymic epithelial cells. Sci Rep. 2015;5:12895. doi: 10.1038/srep12895. - DOI - PMC - PubMed
    1. Calder AE, Hince MN, Dudakov JA, Chidgey AP, Boyd RL. Thymic involution: where endocrinology meets immunology. Neuroimmunomodulation. 2011;18:281–289. doi: 10.1159/000329496. - DOI - PubMed

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