Topoisomerase 1 is required for the development and function of thymus

Area of Science:

• Immunology
• Developmental Biology
• Genetics

Background:

• Thymus organogenesis is essential for T cell maturation.
• The role of Topoisomerase 1 (Top1) in thymus development is not well understood.

Purpose of the Study:

• To investigate the function of Top1 in thymus development and T cell homeostasis.
• To identify the molecular mechanisms underlying Top1's role in thymic epithelial cells (TECs).

Main Methods:

• Generation of a mouse model with Top1 deletion in TECs.
• Transcriptomic analysis to identify Top1's transcriptional targets.
• Flow cytometry to analyze peripheral immunological compartments.

Main Results:

• Biallelic loss of Top1 in TECs leads to congenital thymic aplasia and severe T cell immunodeficiency.
• Top1 deletion results in a loss of αβ T cells and accumulation of γδ T cells and myeloid cells.
• Residual αβ T cells in Top1-deficient mice are effector and oligoclonal, suggesting self-reactivity.

Conclusions:

• Topoisomerase 1 plays a critical, previously unrecognized role in thymus development and T cell homeostasis.
• Top1 is a potential genetic target for conditions involving altered thymic development and T cell lymphopenia.