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Background: The Bacillus Calmette–Guérin vaccine (BCG) has been associated with beneficial nonspecific effects on infant health. We aimed to examine the effect of BCG at birth on thymic size and the associations between thymic output, circulating lymphocytes, risk of infection, and thymic size. Methods: In infants randomized to BCG or no BCG, thymic index (TI), and thymic/weight index (TWI) were measured by ultrasound at birth and at the age of 3 mo. T cell subpopulations including CD4 + T cells, CD8 + T cells, and recent thymic emigrants (RTEs) were assessed by flow cytometry. Infections up to age 3 mo were parent-reported. Results: BCG vaccination did not affect thymic size at age 3 mo, measured as TI. At birth, the number of lymphocytes, CD4+ T cells, CD8+ T cells, and RTEs were positively associated with TI and TWI. Furthermore, a reduced risk of infections up to age 3 mo was associated with a large thymic size at birth. Conclusion: We found no effect of BCG vaccination on thymic size. The positive association between thymic output, lymphocytes, reduced risk of infections, and TI/TWI suggests that assessment of TI/TWI by ultrasound may be a predictor of the immunological capacity in the newborn.

Despite its importance for generating and maintaining a healthy and broad T cell repertoire, the thymus is exquisitely sensitive to acute damage. Marked thymic involution occurs in response to stimuli as diverse as infection, stress, pregnancy, malnutrition, drug use and cytoreductive chemotherapy. However, the thymus also has a remarkable capacity for repair, although this regenerative capacity declines with age. Endogenous thymic regeneration is a crucial process that allows for the recovery of immune competence after acute damage and delay to this recovery can have important clinical effects. Until recently, the mechanisms that drive endogenous thymic regeneration were not well understood, but recent work in mice has revealed multiple distinct pathways of regeneration and the molecular mechanisms that trigger these pathways after damage. In this Review, we discuss the effects of different types of damage to the thymus, with a focus on an emerging body of work in mice that provides insight into the cellular and molecular mechanisms that regulate endogenous tissue regeneration in the thymus. We also highlight some of the clinical challenges that are presented by dysregulated thymic regeneration. This Review discusses recent advances in our understanding of the biology of endogenous tissue regeneration in the thymus, highlighting the clinical implications of poor thymic recovery.

For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ∼16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power lawmodel with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. This framework provides mechanistic insight into cancer emergence, suggesting that age-related decline in T cell output is a major risk factor.

Despite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and GH secretagogues reverse age-related changes in thymus cytoarchitecture and increase thymopoiesis. GH administration also enhances thymic mass and function in HIV-infected patients. Until now, thymic function has not been investigated in adult GH deficiency (AGHD). The objective of this clinical study was to evaluate thymic function in AGHD, as well as the repercussion upon thymopoiesis of GH treatment for restoration of GH/IGF-1 physiological levels. Twenty-two patients with documented AGHD were enrolled in this study. The following parameters were measured: plasma IGF-1 concentrations, signal-joint T-cell receptor excision circle (sjTREC) frequency, and sj/beta TREC ratio. Analyses were performed at three time points: firstly on GH treatment at maintenance dose, secondly one month after GH withdrawal, and thirdly one month after GH resumption. After 1-month interruption of GH treatment, both plasma IGF-1 concentrations and sjTREC frequency were decreased (p<0.001). Decreases in IGF-1 and sjTREC levels were correlated (r = 0.61, p<0.01). There was also a decrease in intrathymic T cell proliferation as indicated by the reduced sj/beta TREC ratio (p<0.01). One month after reintroduction of GH treatment, IGF-1 concentration and sjTREC frequency regained a level equivalent to the one before GH withdrawal. The sj/beta TREC ratio also increased with GH resumption, but did not return to the level measured before GH withdrawal. In patients with AGHD under GH treatment, GH withdrawal decreases thymic T cell output, as well as intrathymic T cell proliferation. These parameters of thymus function are completely or partially restored one month after GH resumption. These data indicate that the functional integrity of the somatotrope GH/IGF-1 axis is important for the maintenance of a normal thymus function in human adults. ClinicalTrials.gov NTC00601419.

Endogenous thymic regeneration is a crucial function that allows for renewal of immune competence after stress, infection, or immunodepletion. However, the mechanisms governing this regeneration remain poorly understood. We detail such a mechanism, centered on interleukin-22 (IL-22) and triggered by the depletion of CD4⁺CD8⁺ double-positive thymocytes. Intrathymic levels of IL-22 were increased after thymic insult, and thymic recovery was impaired in IL-22—deficient mice. IL-22, which signaled through thymic epithelial cells and promoted their proliferation and survival, was up-regulated by radio-resistant RORy(t)⁺CCR6⁺NKp46⁻ lymphoid tissue inducer cells after thymic injury in an IL-23-dependent manner. Administration of IL-22 enhanced thymic recovery after total body irradiation. These studies reveal mechanisms of endogenous thymic repair and offer innovative regenerative strategies for improving immune competence.

The parathyroid and thymus glands are key components of the endocrine and immune systems, respectively, with intriguing developmental, anatomical, and functional interrelationships. This study starts from the hypothesis that, given their shared embryological origin, it is plausible that the thymus and parathyroid glands interact functionally and may share pathological pathways. The present study explores the developmental pathways, spatial proximity, and potential cross-talk between these glands. Recent studies suggest that parathyroid hormone (PTH) may influence thymic function, including T-cell maturation and immune regulation, while thymic signaling molecules could impact calcium homeostasis and parathyroid activity. Understanding the functional and etiopathogenical relations between these endocrine glands offers new insights into endocrine–immunological crosstalk, and therapeutic approaches targeting disorders such as hypoparathyroidism, thymomas, myasthenia gravis and thymic hypoplasia. Perspectives and conclusion: Future research is essential to discover the molecular mechanisms underpinning this dynamic interrelation and its broader implications for health and disease. Because there is still very little data on this interaction, in-depth studies are necessary on large groups of patients. This research proposes a cross-study of the receptors for the main substances secreted by the two categories of endocrine glands. At the same time, it is essential to carry out an in-depth study on the cervico-pericardial ligaments through the lens of this glandular interaction. These ligaments could contain the main blood and nerve communication pathway between the parathyroids and the glands.

The immune system distinguishes between “self” and “nonself” and remembers dangerous exposures. Elaborate mechanisms control immune responses, but in some cases, the response either does not recognize the danger or causes unwanted autoinflammation. The authors review advances in developing durable immune tolerance.

Unprimed mice harbor a substantial population of ‘memory-phenotype’ CD8 + T cells (CD8-MP cells) that exhibit hallmarks of activation and innate-like functional properties. Due to the lack of faithful markers to distinguish CD8-MP cells from bona fide CD8 + memory T cells, the developmental origins and antigen specificities of CD8-MP cells remain incompletely defined. Using deep T cell antigen receptor (TCR) sequencing, we found that the TCRs expressed by CD8-MP cells are highly recurrent and distinct from the TCRs expressed by naive-phenotype CD8 + T cells. CD8-MP clones exhibited reactivity to widely expressed self-ligands. T cell precursors expressing CD8-MP TCRs showed upregulation of the transcription factor Eomes during maturation in the thymus, prior to induction of the full memory phenotype, which is suggestive of a unique program triggered by recognition of self-ligands. Moreover, CD8-MP cells infiltrate oncogene-driven prostate tumors and express high densities of PD-1, which suggests potential roles in antitumor immunity and the response to immunotherapy. Savage and colleagues show virtual memory CD8 T cells arise in the thymus of replete mice, where their differentiation is a robust TCR-directed process. Clonal analyses show their TCR repertoire is reproducible and distinct from conventional cells and that progeny cells harboring such TCRs infiltrate tumors and express PD-1.

The immune system’s ability to resist the invasion of foreign pathogens and the tolerance to self-antigens are primarily centered on the efficient functions of the various subsets of T lymphocytes. As the primary organ of thymopoiesis, the thymus performs a crucial role in generating a self-tolerant but diverse repertoire of T cell receptors and peripheral T cell pool, with the capacity to recognize a wide variety of antigens and for the surveillance of malignancies. However, cells in the thymus are fragile and sensitive to changes in the external environment and acute insults such as infections, chemo- and radiation-therapy, resulting in thymic injury and degeneration. Though the thymus has the capacity to self-regenerate, it is often insufficient to reconstitute an intact thymic function. Thymic dysfunction leads to an increased risk of opportunistic infections, tumor relapse, autoimmunity, and adverse clinical outcome. Thus, exploiting the mechanism of thymic regeneration would provide new therapeutic options for these settings. This review summarizes the thymus’s development, factors causing thymic injury, and the strategies for improving thymus regeneration.

Aging is a continuous process that induces many alterations in the cytoarchitecture of different organs and systems both in humans and animals. Moreover, it is associated with increased susceptibility to infectious, autoimmune, and neoplastic processes. The thymus is a primary lymphoid organ responsible for the production of immunocompetent T cells and, with aging, it atrophies and declines in functions. Universality of thymic involution in all species possessing thymus, including human, indicates it as a long-standing evolutionary event. Although it is accepted that many factors contribute to age-associated thymic involution, little is known about the mechanisms involved in the process. The exact time point of the initiation is not well defined. To address the issue, we report the exact age of thymus throughout the review so that readers can have a nicely pictured synoptic view of the process. Focusing our attention on the different stages of the development of the thymus gland (natal, postnatal, adult, and old), we describe chronologically the morphological changes of the gland. We report that the thymic morphology and cell types are evolutionarily preserved in several vertebrate species. This finding is important in understanding the similar problems caused by senescence and other diseases. Another point that we considered very important is to indicate the assessment of the thymus through radiological images to highlight its variability in shape, size, and anatomical conformation.