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An essential role for gp39, the ligand for CD40, in thymic selection
T M Foy1, D M Page, T J Waldschmidt
1Department of Microbiology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
The Journal of Experimental Medicine
|November 1, 1995
Summary
gp39-CD40 interactions are crucial for deleting self-reactive T cells during thymic education when antigens are endogenously produced. Blocking these interactions prevents the elimination of specific T cell receptor (TCR) V beta types, impacting immune tolerance development.
Area of Science:
- Immunology
- T cell biology
- Immune tolerance
Background:
- CD40-gp39 interactions are vital for T cell-dependent humoral immunity.
- CD40 is expressed on thymic epithelial cells and dendritic cells, suggesting roles beyond B cell activation.
- Thymic education involves deleting self-reactive T cells from the T cell repertoire.
Purpose of the Study:
- To investigate the role of gp39-CD40 interactions in thymic negative selection.
- To determine if gp39-CD40 signaling is required for the deletion of self-reactive T cells.
- To explore the impact of gp39 function on costimulatory molecule expression during negative selection.
Main Methods:
- Studied six negative selection systems with varying antigen presentation (endogenous vs. exogenous).
- Utilized gp39-deficient mice and anti-gp39 blockade in T cell receptor (TCR) transgenic mice.
- Examined TCR V beta expression and B7-2 costimulatory molecule expression in the thymus.
Main Results:
- Loss of gp39 function blocked negative selection when antigens were endogenously expressed, preventing deletion of specific thymocytes (V beta 3, 11, 12).
- gp39-deficient mice showed altered TCR V beta expression, confirming gp39's role in negative selection.
- Blocking gp39-CD40 interactions prevented deletion of TCR transgenic T cells recognizing endogenously expressed antigens but not exogenously administered antigens.
- gp39 deficiency reduced B7-2 expression in the thymus, suggesting regulation of costimulatory molecules.
Conclusions:
- gp39-CD40 interactions are essential for negative selection of T cells against endogenously produced antigens.
- gp39 may regulate negative selection by influencing the expression of costimulatory molecules like B7-2.
- These findings support a model where TCR engagement and costimulation are critical for deleting T cells recognizing self-antigens produced within the body.