Transforming Growth Factor-beta signaling in αβ thymocytes promotes negative selection.

Area of Science:

• Immunology
• T cell biology
• Autoimmunity

Background:

• Negative selection in the thymus removes self-reactive T cells.
• TCR signaling strength is known to drive negative selection.
• The role of cytokine signaling, like TGF-β, in this process is not well understood.

Purpose of the Study:

• To investigate the contribution of Transforming Growth Factor beta (TGF-β) signaling in thymocytes to T cell negative selection.
• To understand the consequences of impaired TGF-β signaling on T cell development and self-tolerance.

Main Methods:

• Analysis of thymocyte development and negative selection in mice lacking TGF-β signaling in thymocytes.
• Assessment of T cell receptor (TCR) signaling, phenotype, and gene expression (e.g., AIRE).
• Evaluation of peripheral T cell accumulation and induction of autoimmune lesions.

Main Results:

• Absence of TGF-β signaling in thymocytes significantly impairs negative selection.
• Autoreactive T cells escape negative selection, acquire a Th1-like phenotype, and express high CXCR3.
• These cells accumulate aberrantly, fail to sustain AIRE expression, escape medullary selection, and lead to peripheral accumulation and organ autoimmunity.

Conclusions:

• TGF-β signaling within thymocytes is essential for effective T cell negative selection.
• Impaired TGF-β signaling disrupts central T cell tolerance, leading to autoimmunity.
• These findings highlight TGF-β as a critical factor in maintaining T cell self-tolerance.