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Friday 29 April is International Day of Immunology, an opportunity to raise global awareness of the importance of immunology in the fight against disease. Immunology research at the IDRM focuses on revealing the fundamental mechanisms that dictate the development and function of our immune system’s ability to efficiently respond to harmful antigens, while being tolerant towards the body’s own tissues.

IDRM’s developmental immunology research group led by Professor Georg Holländer focuses on the thymus, a specialised organ of the immune system where T-cells mature – an integral part of our immune system. Primarily, the Holländer Lab aims to understand thymic development in order to reveal the conditions that enable regular generation of T-cells that are best placed to detect antigens, without mistakenly attacking normal tissues. By understanding these basic mechanisms, we can ultimately better understand what goes wrong in the context of immunodeficiency, autoimmunity and inflammatory disease.

Postdoctoral Researcher Dr Fabian Klein investigates thymic epithelial cell (TECs) heterogeneity and development. These cells control the development and selection of T-cells. Dr Klein specifically looks at how age- and disease-caused alterations in transcription factor FOXN1 affect TEC development and function, and how this impacts the T-cell selection process. FOXN1 is the vitally important master regulator of thymus epithelial cells. Without FOXN1, there are no TECs, and thus no thymus, meaning no T-cells to ward off disease.

Human thymus section. Image Credit: Stefano MaioHuman thymus section. Image Credit: Stefano Maio
“The impact of the COVID-19 pandemic has shown people how important the immune system is for our daily lives and its practicalities as a highly evolved system of protection against COVID-19. But the immune system has so many other roles in health and disease. International Day of Immunology brings this awareness to the public and allows us to showcase the marvellous beauty of the system, its enormous functional competence and the complexity with which the system operates.”
– Immunology theme lead Professor Georg Holländer

Dr Fabian Klein. Image Credit: Audrey Lilly von MuenchowDr Fabian Klein. Image Credit: Audrey Lilly von Muenchow

Dr Klein has successfully created a surface protein profile of TECs, which has helped resolve their heterogeneity and led to the identification of novel subsets. This advances all other investigations on changes in TEC development and the role of FOXN1 in these processes, and brings us a step closer to understanding the complete genetic makeup of the thymus.

Dr Klein credits these findings to an application of expertise obtained during his previous postdoctoral position where he studied the process of hematopoiesis, and revealed some of the earliest steps in the development of our blood cells. Such knowledge is particularly relevant for stem cell and bone marrow transplantations, and as a basis for understanding how leukemia can evolve as a consequence of disruptions in blood cell development.

Trilineage hematopoiesis (production of platelets, red blood cells and white blood cells) which also shows myelomonocytic cells observed in a chronic form of leukemia. Image Credit: Mikael HäggströmTrilineage hematopoiesis (production of platelets, red blood cells and white blood cells) which also shows myelomonocytic cells observed in a chronic form of leukemia. Image Credit: Mikael Häggström

In a newly published paper in Nature Immunology first authored by Dr Klein, the developmental hierarchy during early hematopoiesis, where the critical steps of stem-cell differentiation take place, was redefined. Dr Klein and his team identified the bona fide multipotent progenitor compartment that has lost the self-renewal capacity of hematopoietic stem cells (HSCs) but maintained the capacity to generate all blood cell types. They also defined the precise step where alternative cell fates are lost across all lineages.

Dr Klein said: “At the first step in differentiation, the stem cell loses its capacity to regenerate itself, and becomes a multipotent progenitor that still gives rise to all the various blood cell types. We were able to find a marker – called ESAM - to clearly define the multipotent progenitor as a next step after the hematopoietic stem cell. Moreover, we showed that downregulation of ESAM marks the loss of the potential to differentiate into all blood cell types. This is the first time these steps have been precisely defined.”

Read the full paper “Dntt expression reveals developmental hierarchy and lineage specification of hematopoietic progenitors.”

 

Dr Klein was able to apply his expertise on hematopoiesis to the development of thymic epithelial cells. Resolving the heterogeneity of TEC, in a similar fashion to early hematopoietic progenitors, is essential to uncovering the precise developmental and functional roles of FOXN1.  Where ESAM marks multipotent progenitors that are crucial to the existence of our blood cells, including the protective white blood cells, FOXN1 is the foundation for T-cells and the entire adaptive immune system.

“In my opinion, combining knowledge and experience from various immunological disciplines with the latest technological advances is essential to ultimately revealing the development and complexity of all functional layers of the immune system. 

– Dr Fabian Klein

Mouse thymus section. Image Credit: Stefano MaioMouse thymus section. Image Credit: Stefano Maio

 

For more information on IDRM immunology research, read our Featured Member of the Month profile - Dr Fatima Dhalla of the Holländer Group