Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla

Area of Science:

• Immunology
• T cell development
• Thymic selection

Background:

• The thymic medulla is traditionally considered the primary site for negative selection of T cells.
• The role of the thymic cortex in negative selection, particularly concerning ubiquitous self-antigens, remains controversial.
• Cortical epithelial cells are known to be crucial for positive selection.

Purpose of the Study:

• To investigate the site and mechanism of negative selection for self-reactive thymocytes encountering ubiquitous self-antigens in the thymic cortex.
• To determine the specific antigen-presenting cells responsible for inducing apoptosis during negative selection in the cortex.

Main Methods:

• Utilized the HY(cd4) mouse model with timed T cell receptor (TCR) expression and a ubiquitous self-antigen.
• Analyzed the location and kinetics of clonal deletion (apoptosis) in vivo.
• Investigated the role of cortical epithelial cells and CD11c(+) cortical dendritic cells in TCR activation and apoptosis.

Main Results:

• Demonstrated that clonal deletion of self-reactive thymocytes occurs unambiguously in the thymic cortex.
• Found that apoptosis was activated asynchronously relative to TCR activation.
• Cortical epithelial cells efficiently induced TCR activation but not apoptosis; rare CD11c(+) cortical dendritic cells were preferentially associated with deleted thymocytes.
• Elimination of these dendritic cells impaired thymocyte deletion.

Conclusions:

• Negative selection of self-reactive thymocytes can occur in the thymic cortex.
• Cortical epithelial cells are involved in TCR activation, but cortical dendritic cells play a critical role in mediating apoptosis during negative selection.
• This finding refines our understanding of T cell development and self-tolerance induction within the thymus.