RRAS2 shapes the TCR repertoire by setting the threshold for negative selection

Area of Science:

• Immunology
• Molecular Biology
• Autoimmunity

Background:

• T cell selection in the thymus is crucial for immune tolerance.
• Signal strength from T cell receptor (TCR) affinity determines positive or negative selection.
• Dysregulated T cell selection can lead to autoimmunity.

Purpose of the Study:

• To investigate the role of the GTPase RRAS2 in T cell selection.
• To determine the impact of RRAS2 deletion on autoimmune disease models.

Main Methods:

• Gene deletion of RRAS2 in mice.
• Analysis of T cell selection markers and affinity.
• Assessment of disease severity in models of inflammatory bowel disease (IBD) and experimental autoimmune encephalomyelitis (EAE).

Main Results:

• RRAS2 deletion led to enhanced negative selection and increased positive selection markers.
• Rras2 mice exhibited resistance to IBD and MOG-induced EAE.
• T cells in Rras2 mice showed reduced affinity for MOG/I-A^b.
• TCR repertoire analysis revealed alterations in TRAV locus, VJ combinations, and CDR3α sequences.

Conclusions:

• RRAS2 plays a significant role in regulating T cell selection.
• Enhanced negative selection due to RRAS2 deficiency confers protection against autoimmunity.
• Specific TCR VJ combinations and CDR3α sequences may be involved in autoimmune pathogenesis.