A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development

Area of Science:

• Immunology
• Neuroscience
• Genetics

Background:

• The zinc finger transcription factor BCL11B is crucial for T cell development and neurogenesis.
• A patient with T cell deficiency and neurological disorders presented a BCL11B variant (BCL11B^N441K).

Purpose of the Study:

• To investigate the functional impact of the BCL11B^N440K mutation in mice.
• To elucidate the pathogenic mechanism underlying T cell deficiency and neurological disorders associated with this mutation.

Main Methods:

• Generated mice with the Bcl11b^N440K mutation.
• Analyzed thymocyte populations, focusing on NKp46+ cells.
• Assessed neuronal populations, specifically TBR1+ neurons in the neocortex.
• Investigated protein interactions between BCL11B, BCL11A, and TCF1.

Main Results:

• Mice with Bcl11b^N440K exhibited NK/group 1 innate lymphoid cell (ILC1)-like cells in the thymus and reduced TBR1+ neurons.
• The mutant BCL11B-N440K protein was found to interfere with BCL11A function through heterodimerization.
• The mutation weakened the interaction between BCL11B and T cell factor 1 (TCF1), promoting NK/ILC1-like cell differentiation.

Conclusions:

• The BCL11B^N440K mutation disrupts normal T cell development and neurogenesis.
• The mutant BCL11B protein interferes with BCL11A's role in suppressing non-T lymphoid cell development.
• This study reveals the molecular mechanism of BCL11B-associated disorders and highlights BCL11A's function.