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iNKT cells (invariant natural killer T cells) are special T cells that bridge innate and adaptive immunity, and although the number of cells is scarce, they play a very important role
in fighting cancer and infection.
iNKT cells have long been thought to be tissue-resident immune cells, regulating local and systemic immune effects
.
Their powerful function comes from their ability to directly kill target cells, as well as their ability to rapidly secrete large amounts of cells and inflammatory factors and activate and enhance other immune cells
within the tumor microenvironment.
Therefore, iNKT cells are currently promising immune cells
in anti-tumor immunotherapy.
However, it is also unclear
how iNKT cells acquire innate-like lymphocyte characteristics that differ from T cells.
Interleukin 15 (IL-15) is an important cytokine that acts on both innate and adaptive immunity, secreted by unique stromal cells and myeloid cells in each tissue, which has a very important function in anti-tumor and anti-infection immunity, and is also a very potential cytokine
in anti-tumor immunotherapy.
IL-15 regulates the differentiation, proliferation, activity, and immune effects
of iNKT cells, natural killer cells (NK cells) and T cells.
However, how IL-15 regulates iNKT cells in the immune microenvironment of various tissues is not clear
.
Recently, the team of Guangwei Cui and Koichi Ikuta of Kyoto University in Japan published a report entitled A circulating subset of iNKT cells mediates antitumor and antiviral immunity in Science Immunology Research papers
.
This study is the first to discover a subpopulation of circulating iNKT cells in vivo, and reveals the characteristics of this cell subset and the differentiation mechanism regulated by IL-15 within the thymic immune microenvironment, as well as its efficient anti-tumor and antiviral immune functions
.
First, using the natural killer cell receptor CD244 (2B4) and chemokine receptor CXCR6 as markers, the research team found three subsets of iNKT cells in the thymus and named them C2 iNKT cells (CD244+).
CXCR6+), C1 iNKT cells (CD244−CXCR6+) and C0 iNKT cells (CD244−CXCR6−)
。 Through whole transcriptome sequencing and cell flow cytometry, the authors found that C2 iNKT cells in mice in a steady state are highly expressed with cell killing effector molecules such as IFN-γ and Granzyme, and highly express cell migration and activation related factors, and have very similar characteristics
to NK cells.
C1 iNKT cells have high expression of inducible T cell co-stimulatory factors such as ICOS, so they are closer to naïve T cells
.
At the same time, the Parabiosis model revealed that C2 iNKT cells are the newly discovered subpopulation of circulating iNKT cells, while C1 iNKT cells are traditional tissue-resident iNKT cell subsets
.
Importantly, the authors confirmed the presence of a subset of CD244+CXCR6+C2 iNKT cells in humans and found that they had similar characteristics to C2 iNKT cells in mice, i.
e.
, high expression of cell killer effector molecules and cell activating factors
.
Further, by constructing various tissue-specific IL-15 knockout mouse models, the research team found that C2 iNKT cells only disappeared in thymic epithelial cell-specific IL-15 knockout mice, indicating that IL-15 (Thymic IL-15 niche) in the thymic microenvironment was against C2 The differentiation of iNKT cells plays a crucial role
.
Intrathymic injection and in vitro directed cell-induced differentiation experiments revealed that C0 iNKT cells are precursor cells
of C2 iNKT cells and C1 iNKT cells.
In order to study the function of newly discovered circulating C2 iNKT cells, the authors used melanoma lung metastasis and influenza virus infection as models, combined with thymic epithelial cell-specific IL-15 gene knockout mice and C2 iNKT cell transplantation experiments, and found that the novel circulating C2 iNKT cells have more efficient antitumor and antiviral activity
than traditional tissue-resident C1 iNKT cells.
In summary, a new circulating iNKT cell subset is found that is different from the traditional tissue-resident iNKT cell subpopulation, which deepens the understanding
of iNKT cell differentiation and functional heterogeneity in vivo.
It is proposed that a novel circulating iNKT cell subpopulation can achieve stronger immune surveillance function
by virtue of its good in vivo mobility and cell killing and regulatory activities in the immune microenvironment.
This study laid a theoretical foundation
for the development of new methods for anti-tumor and antiviral efficient immune cells based on iNKT cells and IL-15.
Assistant Professor Guangwei Cui of the Department of Virology and Regenerative Medicine Sciences, Kyoto University, Japan, is the first author and co-corresponding author of this paper, and Professor Koichi Ikuta is the co-corresponding author.
The research was also strongly supported
by Professor Katsuyuki Shiroguchi and Dr.
Kenseok Kim of the Institute of Physical and Chemical Research.
Original link:
http://doi.
org/10.
1126/sciimmunol.
abj8760
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