The most detailed map of the developing human thymus reveals how immune responses are formed and sustained early in life, which is crucial for addressing immunodeficiency, autoimmunity, and cancer.
By creating the inaugural spatial atlas of the developing human thymus—an essential organ that prepares immune cells to combat infections and cancer—researchers discovered that the groundwork for lifelong immunity starts sooner than previously believed.
A team from the Wellcome Sanger Institute, in collaboration with Ghent University in Belgium and the National Institutes of Health’s National Institute of Allergy and Infectious Diseases, identified significant variations in how immune cells are developed. This knowledge could pave the way for scientists to engineer immune cells outside the body, aiding in cancer treatment, countering age-related immune decline, or lowering the risk of transplant rejection.
The study, published today (November 20) in Nature, is a part of the global Human Cell Atlas (HCA) initiative, aimed at cataloging every cell type in the human body1. Insights from examining how thymus samples evolve before and after birth may assist future researchers in constructing an artificial thymus, which is the initial step toward engineering therapeutic immune cells for older individuals or those with weakened immune systems.
This research is one among a collection of over 40 HCA publications in Nature Portfolio journals, marking a significant advancement in our grasp of human biology.
The immune system shields the body from infections and cancer using a diverse array of T cells, a type of white blood cell. For T cells to function properly, they must be trained to identify threats while avoiding harm to the body’s healthy cells. The thymus, a small organ located behind the breastbone, is where this vital T cell training happens.
If the thymus does not function properly, it can lead to weakened immune defenses or autoimmune diseases, where the body erroneously attacks its own healthy tissues, resulting in conditions like type 1 diabetes or rheumatoid arthritis.
Despite its critical role, our understanding of early thymus development is limited, as it is predominantly active during infancy and gradually diminishes throughout life2. Investigating its early development is essential for understanding why immune responses decline with age, which makes older individuals more susceptible to infections and less responsive to vaccinations3.
In this recent study, Wellcome Sanger Institute researchers and their colleagues analyzed thymus and T cell development in samples from eleven weeks post-conception to three years old4 using single-cell sequencing and sophisticated spatial mapping methods.
They found that the basic structure and functionality of the thymus is established as early as twelve weeks post-conception, indicating that factors during early pregnancy may significantly influence lifelong immune capabilities more than previously acknowledged.
The team identified crucial differences in the development of various T cell types5—some of which help coordinate immune responses by directing other immune cells, while others directly attack infected or cancerous cells. This new understanding could guide the development of T cell engineering therapies that enhance immunity for cancer treatment or suppress it for autoimmune diseases and transplant procedures.
Additionally, the researchers identified locations of progenitor cells that develop into important supportive cells within the thymus, which mimic the body’s own environment, ensuring T cells do not respond adversely to self. This discovery could aid in the future creation of an artificial thymus, facilitating regenerative immune therapies for older adults or individuals with compromised immune systems.
A significant outcome of the study was the establishment of an innovative high-resolution spatial mapping technique named OrganAxis, which allows for a detailed comparison of thymus samples across different developmental stages, achieving a resolution previously unattained. This method could also be utilized to study other organs that undergo significant changes over time or vary widely among individuals, such as the liver or kidneys.
Dr. Nadav Yayon, co-first author of the study and formerly at the Wellcome Sanger Institute and EMBL-EBI, now at the Cambridge Stem Cell Institute, University of Cambridge, stated: “The thymus is critically important for establishing lifelong immunity, yet previously it was nearly impossible to compare its developmental stages, as they appeared drastically different. OrganAxis enables us to integrate distinct spatial datasets to reveal hidden features that may be overlooked when examined individually. By using key structures as reference points, akin to how hikers use landmarks, we can now observe the formation of structures early on, tracking T cell training over time.”
Dr. Veronika Kedlian, co-first author of the study, also formerly at the Wellcome Sanger Institute and now at the Cambridge Stem Cell Institute, University of Cambridge, commented: “Our atlas of healthy thymus development may inspire new methods to enhance immunity, particularly in older adults or those with thymus disorders. We are currently leveraging this resource to investigate age-related immune changes and conditions such as DiGeorge syndrome, where infants are born without a functional thymus and face a heightened risk of infections.”
Dr. Sarah Teichmann, the senior author of the study and a co-founder of the Human Cell Atlas, who previously worked at the Wellcome Sanger Institute and is now based at the Cambridge Stem Cell Institute, University of Cambridge, remarked: “This thymus map is the first comprehensive model of a human organ at single cell resolution with extensive transcriptomic data. It represents a vital component of our objective to understand human biology one cell at a time in the Human Cell Atlas. By grasping how the thymus educates immune cells from their earliest phases, we gain insights into immune deficiencies and autoimmune disorders. This map provides a significant perspective for developing therapies aimed at strengthening or rectifying immune responses.”
The developing human thymus spatial data is available for exploration through this web portal: https://cellxgene.cziscience.com/collections/fc19ae6c-d7c1-4dce-b703-62c5d52061b4
- This study is part of the international Human Cell Atlas (HCA) consortium, which aims to create thorough reference maps of all human cells to understand human health better and to aid in diagnosing, monitoring, and treating diseases. The HCA is a collaborative international effort with the mission to compile comprehensive reference maps of human cells—the basic building blocks of life—as a foundation for comprehending human health and for disease-related actions. The HCA community comprises more than 3,500 members from over 100 countries who are collaborating to develop a diverse and accessible Atlas for the betterment of humanity. Discoveries from this initiative are already influencing medical applications ranging from diagnostics to drug discovery, potentially revolutionizing biology and healthcare and ushering in an era of precision medicine. https://www.humancellatlas.org
- The thymus is particularly notable due to its development and function. Children born without a functioning thymus lack T cells and are extremely susceptible to infections, such as those with severe immune deficiencies like SCID. Conversely, those who have a healthy thymus surgically removed to access the heart during a procedure manage to retain a functioning immune system. This illustrates the thymus’s crucial role early in life for T cell training and establishing lifelong immunity. Over time, as the thymus ages, its T cell development areas are replaced with fat, leading to reduced T cell production and a weakened immune system.
- C. Kellogg (2020) ‘The role of the thymus in COVID-19 disease severity: implications for antibody treatment and immunization’ Human Vaccines & Immunotherapeutics. DOI: 10.1080/21645515.2020.1818519
- Thymus samples were sourced from the University of Newcastle, National Institutes of Health, and Ghent University, Belgium.
- In the thymus, specific cells assist in training developing T cells, which are essential for our immune system. Certain cells within the thymus resemble the body’s own cells, teaching T cells to distinguish what is ‘normal’ from what is not; others act as gatekeepers to verify that T cells have successfully finished their training and are ready to progress. This process is critical—if these cells fail to deliver correct signals, T cells may not learn properly, leading the immune system to mistakenly target healthy tissues and resulting in autoimmune diseases. These cells serve as ‘teachers’ in the thymus, presenting a variety of self-proteins to developing T cells. A notable finding of this study was that T cells destined to become CD8 cells—recognized for eliminating infected or malignant cells—remain in the thymus’s cortex for a longer duration before advancing to the next developmental phase compared to CD4 cells, which help regulate immune responses.
