10 Jul 2025
An international team led by Ludger Klein has provided important insights into the maturation of T cells in the thymus, which is a central process in the development of a functioning immune system.
© Jan Greune
The study, led by Prof Ludger Klein at the Biomedical Center (BMC) of LMU Munich and Dr Stephen Daley (Australia) addresses a long-known immunological paradox: the recognition of the body's own structures (“self”) is essential for the development of CD4+ T cells in the thymus - an organ specialized for this task - but also harbours dangers. A misdirected immune response against the body's own tissue can have serious consequences. Such incorrect reactions can be observed, for example, in autoimmune diseases such as multiple sclerosis or type 1 diabetes.
T cells recognize foreign structures via so-called antigen receptors - a process that enables them to specifically combat pathogens. Before entering the bloodstream and circulating throughout the body, T cells must pass an aptitude test in the thymus. They only survive if their receptors can recognise MHC (major histocompatibility complex) molecules with bound peptides — this step is known as 'positive selection'. At the same time, they must not bind too strongly to the body's own ("self") structures in order to prevent autoimmune reactions. Such cells are eliminated in a second step known as 'negative selection'.
Two hypotheses on selection - and a new finding
A common explanation assumes that the strength of recognition is decisive. Weak binding to endogenous peptides results in survival, whereas strong binding results in programmed cell death. However, an alternative hypothesis suggests that the two selection processes are mediated by different cell types that present different peptide fragments, particularly during positive selection. In this context, cortical thymic epithelial cells appear to play a special role, as they utilise an atypical form of peptide processing to load their MHC molecules.
A key part of this process involves the enzyme lysosomal cysteine protease cathepsin L (CTSL), which is an active protease found in the epithelial cells of the thymus.
To investigate its function in more detail, Klein's team deactivated the cathepsin L gene specifically in the thymus. The consequences were clear: firstly, the diversity of the resulting T cell receptors was severely restricted — indicating that many potential T cells had not passed positive selection — and secondly, the surviving T cells showed functional deficits and reduced survival after development.
'Altered self' as a central element of T cell formation
These results suggest that positive selection is not simply mediated by 'normal' self, but by 'altered' self — i.e. peptides produced by specialised processing in the thymus that differ from those found in other tissues. “Our study shows that these modified peptides not only determine whether a T cell survives, but also its long-term functional properties,” explains Klein. “The interaction with ‘altered self’ appears to be an essential step in building a broad-based and functional T cell repertoire.”
These new findings significantly contribute to our understanding of central immune selection and could also have therapeutic applications in the long term, for example in the treatment of autoimmune diseases or immunotherapy.
Publication: E. Petrozziello et al.: Cathepsin L-dependent positive selection shapes clonal composition and functional fitness of CD4+ T cells. Nature Immunology 2025