Innate iNKT cells: from biological insight to clinical impact
File(s)
Published version
Author(s)
Rotolo, Antonia
Mason, Nicola J
Exley, Mark A
Type
Journal Article
Abstract
Over the past 30 years, work of immunologists worldwide has phenotypically and
functionally defined “Natural Killer T cells” (NKT) and their subsets, including
“invariant Natural Killer T cells” (iNKT). NKT cells make up a substantial fraction of
T cells that express NK cell markers and have TCRs restricted to either
conventional MHC molecules or the monomorphic CD1d molecule. Among
these, iNKT cells are CD1d-restricted and more common within NKT cells than T
cells without NK markers. While the definition of NKT cells, whether based on
phenotype, function, or both, remains a topic of debate, iNKT cells represent a
distinct T cell population characterized by a recurrent, conserved TCR
rearrangement (TRAV10–TRAJ18 in humans) paired with a limited Vb repertoire
(mostly encoded by TRBV25-1 in humans). iNKT cells are restricted by CD1d,
which, unlike CD1a-c molecules, is expressed not only on professional antigen presenting cells and thymocytes but also on certain non-hematopoietic somatic
tissues, both normal and neoplastic. Like all CD1 family members, CD1d presents
various lipid antigens by accommodating their long hydrophobic tails in deep
binding pockets, in contrast to the shallow peptide grooves of conventional MHC
molecules. However, the ligand repertoire of CD1d is distinct from that of CD1a c. This review focuses on CD1d-restricted iNKT cells. Activation of iNKT cells via
their semi-invariant TCR, often in synergy with NK receptors and other co stimulatory molecules, triggers a rapid, polyfunctional response. Unlike
conventional MHC-restricted T cells, individual iNKT cells can simultaneously
produce both Th1- and Th2-type cytokines and exert cytotoxic activity in an
immune synapse-directed fashion. Through this combination of direct
cytotoxicity and cytokine-mediated immunomodulation, iNKTs can eliminate
target cells while activating myeloid and other lymphoid populations to amplify
immune responses. Their versatility has fueled growing interest in harnessing
iNKT cells across inflammatory, infectious, and oncological diseases, where
early-phase studies have demonstrated their safety and preliminary efficacy.
Moreover, because they are restricted by the non-polymorphic CD1d molecule
and possess immune-regulatory properties, iNKT cells lack graft-versus-host
potential, making them ideal candidates for allogeneic, off-the-shelf therapies.
This review summarizes how iNKT cells are being reimagined as innovative tools
for immune intervention across a range of clinical settings.
functionally defined “Natural Killer T cells” (NKT) and their subsets, including
“invariant Natural Killer T cells” (iNKT). NKT cells make up a substantial fraction of
T cells that express NK cell markers and have TCRs restricted to either
conventional MHC molecules or the monomorphic CD1d molecule. Among
these, iNKT cells are CD1d-restricted and more common within NKT cells than T
cells without NK markers. While the definition of NKT cells, whether based on
phenotype, function, or both, remains a topic of debate, iNKT cells represent a
distinct T cell population characterized by a recurrent, conserved TCR
rearrangement (TRAV10–TRAJ18 in humans) paired with a limited Vb repertoire
(mostly encoded by TRBV25-1 in humans). iNKT cells are restricted by CD1d,
which, unlike CD1a-c molecules, is expressed not only on professional antigen presenting cells and thymocytes but also on certain non-hematopoietic somatic
tissues, both normal and neoplastic. Like all CD1 family members, CD1d presents
various lipid antigens by accommodating their long hydrophobic tails in deep
binding pockets, in contrast to the shallow peptide grooves of conventional MHC
molecules. However, the ligand repertoire of CD1d is distinct from that of CD1a c. This review focuses on CD1d-restricted iNKT cells. Activation of iNKT cells via
their semi-invariant TCR, often in synergy with NK receptors and other co stimulatory molecules, triggers a rapid, polyfunctional response. Unlike
conventional MHC-restricted T cells, individual iNKT cells can simultaneously
produce both Th1- and Th2-type cytokines and exert cytotoxic activity in an
immune synapse-directed fashion. Through this combination of direct
cytotoxicity and cytokine-mediated immunomodulation, iNKTs can eliminate
target cells while activating myeloid and other lymphoid populations to amplify
immune responses. Their versatility has fueled growing interest in harnessing
iNKT cells across inflammatory, infectious, and oncological diseases, where
early-phase studies have demonstrated their safety and preliminary efficacy.
Moreover, because they are restricted by the non-polymorphic CD1d molecule
and possess immune-regulatory properties, iNKT cells lack graft-versus-host
potential, making them ideal candidates for allogeneic, off-the-shelf therapies.
This review summarizes how iNKT cells are being reimagined as innovative tools
for immune intervention across a range of clinical settings.
Date Issued
2025-09-10
Date Acceptance
2025-08-08
Citation
Frontiers in Immunology, 2025, 16
ISSN
1664-3224
Publisher
Frontiers Media S.A.
Journal / Book Title
Frontiers in Immunology
Volume
16
Copyright Statement
© 2025 Rotolo, Mason and Exley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41000376
Subjects
ACTIVATION
allogeneic cells
ANTITUMOR-ACTIVITY
CANCER-PATIENTS
CD1
CD1d
COMBINATION THERAPY
COVID-19
graft versus host disease (GVHD)
Immunology
invariant natural killer T (iNKT) cell
INVARIANT NKT CELLS
KILLER-T-CELLS
Life Sciences & Biomedicine
NKT cell
off-the-shelf cells
PHASE-I
POSITIVE SELECTION
RECEPTOR-ALPHA-CHAIN
Science & Technology
VERSUS-HOST-DISEASE
Publication Status
Published
Coverage Spatial
Switzerland
Article Number
1653183
Date Publish Online
2025-09-10