Innate iNKT cells: from biological insight to clinical impact

Area of Science:

• Immunology
• Cellular Biology
• Immunotherapy

Background:

• Natural Killer T cells (NKT) and invariant NKT (iNKT) cells are immune cells with NK cell markers and specific T cell receptors (TCRs).
• iNKT cells are CD1d-restricted, a distinct characteristic that influences their antigen presentation and tissue distribution compared to other NKT cells.
• The precise definition of NKT cells remains debated, but iNKT cells are recognized by their conserved TCR rearrangement and limited Vβ repertoire.

Purpose of the Study:

• To review the characteristics and therapeutic potential of CD1d-restricted invariant Natural Killer T cells (iNKT).
• To highlight the unique antigen presentation by CD1d molecules, which bind lipid antigens.
• To explore the application of iNKT cells in treating inflammatory, infectious, and oncological diseases.

Main Methods:

• Phenotypic and functional characterization of NKT and iNKT cells.
• Analysis of TCR and Vβ repertoire in iNKT cells.
• Review of CD1d-mediated antigen presentation, focusing on lipid antigens.
• Examination of iNKT cell activation, cytokine production (Th1/Th2), and cytotoxic activity.
• Assessment of iNKT cell potential in preclinical and early clinical studies.

Main Results:

• iNKT cells exhibit a semi-invariant TCR and are restricted by the CD1d molecule, which presents lipid antigens.
• Upon activation, iNKT cells produce both Th1 and Th2 cytokines and possess cytotoxic capabilities.
• iNKT cells can eliminate target cells and modulate immune responses, amplifying anti-pathogen and anti-tumor immunity.
• Early studies indicate iNKT cell therapy is safe and shows preliminary efficacy in various diseases.
• iNKT cells lack graft-versus-host potential due to CD1d restriction, making them suitable for allogeneic therapies.

Conclusions:

• Invariant Natural Killer T cells are a distinct immune population with significant therapeutic promise.
• Their ability to bridge innate and adaptive immunity via CD1d-restricted lipid antigen presentation is key to their function.
• iNKT cells represent a versatile and safe platform for immune intervention in diverse clinical settings, including off-the-shelf allogeneic therapies.