Dual-receptor T cells expressing one self-restricted TCR

Area of Science:

• Immunology
• T cell biology
• Molecular immunology

Background:

• T cell development in the thymus involves T cell receptor (TCR) gene rearrangement and selection based on interactions with major histocompatibility complex (MHC) molecules.
• Recent research suggests a significant proportion of peripheral T cells express two TCRs, both functional, with implications for autoimmunity.
• The generation and function of dual-TCR expressing T cells remain incompletely understood.

Purpose of the Study:

• To investigate the generation of dual-receptor T cells in a specific mouse model.
• To determine if a non-functional TCR can be rescued by the co-expression of an endogenous TCR.
• To re-evaluate the in vivo specificity and regulatory requirements of dual-TCR T cells.

Main Methods:

• Utilized class II-deficient mice expressing a class II-restricted AND T cell receptor transgene (TCRtg).
• Analyzed T cell development and TCR expression in these genetically modified mice.
• Investigated the role of endogenous TCRs in positive selection on class I MHC molecules.

Main Results:

• Dual-receptor T cells were readily generated in class II-deficient mice expressing the AND TCR transgene.
• T cells developed by co-expressing non-transgenic endogenous TCRs that enabled positive selection on class I MHC molecules.
• The expression of a second TCR rescued developing T cells when the primary TCR failed positive selection on self MHC.

Conclusions:

• The failure of a rearranged TCR to engage self-MHC molecules can be overcome by expressing a second, endogenous TCR.
• Many dual-receptor T cells may function as mono-specific cells in vivo, possessing only one self-MHC restricted TCR.
• These findings suggest that dual-TCR T cells may not necessitate unique regulatory mechanisms to prevent autoreactivity.