Two signals are required for negative selection of CD4+CD8+ thymocytes

Area of Science:

• Immunology
• T cell biology
• Cellular signaling

Background:

• Mature T cell activation requires two signals: T cell receptor (TCR) and co-stimulatory receptor engagement with antigen-presenting cells (APCs).
• The signals necessary for negative selection of autoreactive thymocytes remain largely unknown.
• B7/BB1 on APCs costimulates T cell activation via CD28 or CTLA4 on T cells.

Purpose of the Study:

• To investigate the signals required for negative selection of autoreactive thymocytes.
• To determine the role of antigen-presenting cells (APCs) and co-stimulatory molecules in thymocyte deletion.

Main Methods:

• Utilized an in vitro culture system with thymocytes from transgenic mice expressing a specific TCR.
• Cultured thymocytes with murine fibroblast lines engineered to express MHC class II.
• Analyzed the effects of anti-TCR antibodies and APCs on CD4+CD8+ (DP) thymocyte programmed cell death.

Main Results:

• Negative selection of DP thymocytes is an Ag-dependent programmed cell death process.
• Both TCR and APC-dependent stimuli are required for DP thymocyte deletion.
• Anti-TCR antibodies alone induced a DPdull phenotype, but APC addition was necessary for deletion.
• B7 was found not to be the APC-dependent signal mediating deletion.

Conclusions:

• Negative selection of autoreactive thymocytes is a two-step process.
• Step 1: TCR stimulation leads to CD4 and CD8 downregulation on DP thymocytes.
• Step 2: An unknown APC ligand interacts with a DP thymocyte receptor to induce deletion.