Does negative selection involve accumulation of self-reactive thymocytes in thymic rosettes?

Area of Science:

• Immunology
• Cell Biology
• Developmental Biology

Background:

• Thymic rosettes are natural associations between thymocytes and stromal cells (macrophages or dendritic cells).
• T cell deletion in the thymus is crucial for immune tolerance and preventing autoimmunity.
• Specific T cell populations are deleted based on their T cell receptor (TcR) interactions with self-antigens.

Purpose of the Study:

• To investigate whether selective association of thymocytes with stromal cells precedes negative selection (deletion).
• To determine if stromal cells present antigens (e.g., Mlsa gene products, IE class II MHC molecules) that lead to T cell deletion.
• To examine the role of thymic stromal cells in the deletion of autoreactive T cells.

Main Methods:

• Isolation of thymic rosettes from mouse strains using collagenase digestion and unit-gravity elutriation.
• Comparison of rosettes from genetically modified mouse strains (lacking specific V beta-bearing thymocytes) with control strains.
• Functional assays using T-hybridomas to assess the stimulatory activity of rosette preparations.

Main Results:

• Stromal components of thymic rosettes were poor presenters of Mlsa gene products.
• No enrichment of thymocytes with specific V beta TcR levels was observed in rosettes from Mlsa-bearing strains.
• No selective association of thymocytes bearing V beta 17a was detected in rosettes from IE-positive strains.

Conclusions:

• The results argue against physical binding and immobilization on stromal cells as a mechanism for T cell deletion.
• Stromal cells may deliver a rapid signal during a transient association, leading to subsequent T cell deletion.
• This suggests a model where deletion occurs without prolonged physical interaction with thymic stromal cells.