Mouse Thymus: Anatomy, T-Cell Maturation, and Immunology

The thymus is essential for immune system development, serving as the primary site for T-cell maturation. In mice, it is widely studied due to its similarities with human immunology, making it a valuable model for research on immunity and disease resistance. Understanding its function provides insight into adaptive immunity and immune disorders.

Research on the mouse thymus has revealed key processes that shape T-cell populations and influence immune function. Examining its structure, cellular interactions, and regulatory mechanisms clarifies how T-cells develop and contribute to immune responses.

Anatomical Structure And Cell Composition

The mouse thymus is a bilobed organ located in the anterior mediastinum, just above the heart and behind the sternum. Each lobe is enclosed by a thin connective tissue capsule, which extends inward to form trabeculae that divide the thymus into smaller lobules. These lobules contain two key regions: the outer cortex and inner medulla, each supporting different stages of T-cell development. The cortex is densely packed with immature thymocytes, while the medulla houses more mature T-cells and stromal cells that facilitate final selection and maturation.

In the cortex, thymocytes interact closely with cortical thymic epithelial cells (cTECs), which present self-peptides bound to major histocompatibility complex (MHC) molecules. This allows for the initial screening of thymocytes based on their ability to recognize self-MHC. A network of fibroblasts and extracellular matrix components supports thymocyte migration and proliferation, while cortical capillaries form a selective blood-thymus barrier, restricting circulating antigens and ensuring a controlled environment for early T-cell development.

As thymocytes move toward the medulla, they encounter medullary thymic epithelial cells (mTECs) and dendritic cells, which help eliminate autoreactive T-cells. mTECs express the autoimmune regulator (AIRE) protein, which facilitates the presentation of a broad range of self-antigens—critical for establishing central tolerance and preventing autoimmunity. The medulla also contains Hassall’s corpuscles, concentric whorls of epithelial cells believed to regulate thymocyte apoptosis and immune tolerance.

T-Cell Differentiation And Selection

T-cell development follows a structured sequence of differentiation and selection events that ensure the production of functional yet self-tolerant T-cells. Bone marrow-derived progenitor cells migrate to the thymus, entering the outer cortex as double-negative (DN) cells lacking CD4 and CD8 co-receptors. As they progress through DN stages, they undergo T-cell receptor (TCR) gene rearrangement, mediated by recombination-activating genes (RAG1 and RAG2). Only thymocytes that successfully rearrange a functional TCR β-chain pair with the pre-Tα chain survive, allowing them to proliferate and transition to the double-positive (DP) stage, where they express both CD4 and CD8.

In the DP stage, thymocytes undergo positive selection, ensuring their TCRs can recognize self-MHC molecules. This occurs in the cortex, where cTECs present self-peptides bound to MHC class I and II molecules. Thymocytes that engage MHC molecules with appropriate affinity receive survival signals, while those failing to recognize MHC undergo apoptosis. The strength of TCR-MHC interactions dictates lineage commitment—thymocytes binding MHC class I become CD8+ cytotoxic T-cells, while those recognizing MHC class II differentiate into CD4+ helper T-cells.

Following positive selection, thymocytes migrate to the medulla for negative selection. Here, mTECs and dendritic cells present a diverse array of self-antigens, including tissue-restricted antigens regulated by AIRE. Thymocytes binding these self-antigens with high affinity are eliminated, preventing the survival of autoreactive T-cells. Some thymocytes with moderate self-antigen recognition differentiate into regulatory T-cells (Tregs), which suppress immune responses to self-tissues.

Endocrine Signaling Effects

Hormonal regulation significantly influences thymocyte proliferation, differentiation, and survival. Glucocorticoids, produced by the adrenal glands in response to stress, modulate apoptosis and selection processes. Elevated glucocorticoid levels increase apoptosis of developing thymocytes, particularly at the DP stage, contributing to thymic atrophy under chronic stress.

Thyroid hormones also regulate thymic development. Hypothyroidism in neonatal mice delays thymocyte proliferation and reduces thymic mass, while hyperthyroidism accelerates differentiation. Thyroid hormone receptors in thymic epithelial cells influence gene transcription related to cell cycle progression and metabolism. Thyroid hormone supplementation in aged mice has been shown to partially reverse thymic involution, suggesting a potential approach to mitigating age-related immune decline.

Sex hormones further impact thymic function. Androgens, such as testosterone, contribute to thymic involution, as castration in male mice leads to thymic regeneration and increased thymocyte numbers. This likely results from the removal of androgen-mediated suppression of thymic epithelial cell proliferation. Estrogens influence cytokine production and thymocyte survival, with fluctuations in estrogen levels affecting T-cell export rates. These findings highlight the complex interplay between sex hormones and thymic physiology.

Thymic Regression In Adults

The mouse thymus undergoes age-related regression, marked by a decline in structural integrity and functional capacity. This involution begins early in adulthood, with thymic parenchyma gradually replaced by adipose tissue. Histological analyses show reduced thymic epithelial cell density, fewer thymocytes, and disruption of cortical-medullary architecture. These changes correspond with diminished expression of key transcription factors such as FOXN1, which maintains thymic epithelial cell function. Despite this decline, certain regions retain residual lymphoid activity, suggesting that some degree of thymopoiesis persists.

While thymic involution is often considered inevitable, factors such as nutrition, systemic inflammation, and endocrine fluctuations influence its progression. Caloric restriction in mice has been shown to delay thymic atrophy, possibly by reducing oxidative stress and preserving epithelial integrity. Hormonal interventions, such as growth hormone supplementation, have also demonstrated partial restoration of thymic architecture. However, the molecular signals driving thymic regression remain incompletely understood.

Immunological Significance

The mouse thymus plays a central role in shaping adaptive immunity by generating a diverse T-cell repertoire while ensuring immune self-tolerance. Thymic selection produces T-cells capable of recognizing foreign antigens while minimizing autoimmunity. Disruptions in thymic selection can lead to immunodeficiencies or autoimmune diseases. Studies using genetically modified mice have shown that defects in thymic epithelial cell function or negative selection can result in conditions such as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or severe combined immunodeficiency (SCID).

Even after substantial regression in adulthood, the thymus continues to influence immune responses. Residual thymopoiesis contributes to naïve T-cell renewal, which is particularly relevant during immune recovery following bone marrow transplantation or chemotherapy-induced lymphodepletion. Enhancing thymic activity through cytokine administration, such as interleukin-7 (IL-7), has been shown to improve T-cell reconstitution in immunocompromised mice. Research into thymus-derived regulatory T-cells (Tregs) has also provided insights into their role in controlling immune activation, with implications for therapies targeting inflammatory and autoimmune diseases. The thymus’s lasting impact on immune function underscores its significance in both health and disease.