Recognition of MR1-antigen complexes by TCR Vγ9Vδ2

Area of Science:

• Immunology
• T cell biology

Background:

• T cell receptor (TCR) Vγ9Vδ2 activation typically uses innate-like mechanisms involving butyrophilin 3 (BTN3) and phosphoantigens.
• The capacity of TCR Vγ9Vδ2 cells to recognize antigens presented by classical antigen-presenting molecules in an adaptive manner remains unexplored.

Purpose of the Study:

• To investigate whether TCR Vγ9Vδ2 cells can recognize MR1-antigen complexes.
• To characterize the mechanism and potential role of this recognition in health and disease.

Main Methods:

• Identification and characterization of MR1-autoreactive TCR Vγ9Vδ2 cells.
• TCR gene transfer experiments to confirm antigen recognition.
• Analysis of cell populations in healthy individuals and a patient with autoimmune symptoms.

Main Results:

• MR1-autoreactive TCR Vγ9Vδ2 cells were identified, exhibiting antigen- and CDR3δ-dependent, but butyrophilin-independent activation.
• TCR gene transfer confirmed MR1-antigen recognition, and engineered TCR Vγ9Vδ2 tetramers bound soluble MR1-antigen complexes.
• These autoreactive cells were found at low frequencies in healthy individuals and expanded in a patient with autoimmune disease, releasing pro-inflammatory cytokines.

Conclusions:

• MR1-self-antigen complexes can be recognized by specific TCR Vγ9Vδ2, leading to T cell activation.
• This recognition pathway represents a novel adaptive-like T cell response.
• The presence and activation of these MR1-self-reactive cells may contribute to autoimmune pathogenesis.