WEHI Wednesday Seminar hosted by Professor Daniel Gray
 

Kelin Zhao
PhD Student – Gray Laboratory, Immunology division – Infectious Diseases & Immune Defence division, WEHI (this is a PhD Completion seminar)

Resolving new features of thymic involution and regeneration

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session

The thymus is essential for immunity by directing the development of T cells that fight infection and cancer. Thymic epithelium cells (or TECs) form unique 3D microenvironments that orchestrate this complex process. Curiously, the thymus is the first organ in the body to undergo age-related atrophy, termed thymic involution, characterized by reduced size and degeneration of the microenvironment, resulting in a decline in the output of new T cells. The thymus is also damaged by stressors such as severe infections or cytoablative treatments used to treat cancer. Thymic atrophy is associated with the loss of immune function with age and is a major limitation in recovery from haematopoietic stem/progenitor cell transplantation (HSCT) since T cell deficiency causes life-threatening infections. Interestingly, the thymus is a regenerative organ and restoring thymic function in these settings is a major goal in regenerative medicine. However, the mechanism of age-associated thymic involution and why it impairs regeneration is in not yet understood.

We have used whole organ 3D imaging techniques to interrogate thus mechanism, focussing on TEC during involution and regeneration using novel reporter mice. We find a striking defect in TEC that starts in middle-age and expands with aging. These “age-associated TECs” (aaTECs) were morphologically distinct from their normal, functional TEC counterparts, forming highly compact structures that do not support T cell development. Single-cell RNA-seq analyses identified a unique transcriptional profile in aaTEC, characterised by a partial epithelial-to-mesenchymal transition (pEMT). In addition to directly contributing to age-associated thymic dysfunction, aaTEC expand after acute injury, correlating with their co-opting thymic growth factors and impaired regeneration. Thus, we conclude that the aaTEC is a key feature of thymic involution that limits immune function and regeneration.

All welcome!