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The 2019 Albert Lasker Basic Medical Research Award went to professors Max Cooper and Jacques Miller for their discovery of B and T cells
of the immune system, respectively.
In 1961~1962, Professor Jacques Miller used his self-taught infant thymusctomy to prove for the first time that thymus organs were not dispensable and superfluous organs considered dispensable by the medical community at that time, if the thymus gland of infant mice was surgically removed, the volume of peripheral lymphoid organs of mice in adulthood was greatly reduced [1] , and lack of killer cells responsible for immune rejection [2].
Jacques Miller is recognized by the immunology community as the discoverer
of the T (the first letter of Thymus) cells.
Professor Jacques Miller's follow-up work also found that thymus-derived T cells have both killing functions and the function
of helping B cells produce antibodies.
But he didn't delve further into which group of T cells is killer and which group of T cells is helpful
.
In 1975, four professors, Herbert Oettgen, Lloyd Old, Edward Boyse, and Havey Cantor, revealed that CD8a+CD8b+ (also known as Ly2+Ly3+) T cells have killing functions, while CD4+ (also known as Ly1+) T cells Cells have the function of helping B cell antibody responses and helping killer T cells [3-6].
Since then, CD8a or CD8b have been considered marker molecules for killer T cells, while CD4 has been thought to be a marker molecule for helper T cells
.
In the same year, Professor Joseph Bolen discovered that the intracellular region of the CD8a molecule can bind to Lck [8].
Therefore, the CD8a molecule is not only a marker molecule, the immunological community believes that the CD8a molecule can act as a co-receptor for TCR to enhance the response
of CD8+ T cells.
Many in vitro experiments support the co-acceptor hypothesis of the CD8a molecule, but lack direct support
from in vivo experiments.
The function of the CD8a molecule in vivo remains to be elucidated
.
In 1991, Professor Tak Mak tried to study the function of CD8a molecules in vivo, so he designed CD8a knockout mice and found that CD8a genes are very critical for the development and positive selection of killer T cells in the thymus, and killer T cells cannot complete normal development and positive selection in the CD8a–/– mouse thymus, resulting in CD8a–/– There are no killer T cells in mouse peripheral lymphoid organs[9].
Thus, the function of the CD8a gene in the development of the thymus gland in vivo was elucidated
.
However, the function of the CD8a protein on killer CD8+ T cells in peripheral lymphoid organs has been pending and has not been clarified
by direct in vivo tests.
In 2022, Professor Lieping Chen's group, director of the Yale University Cancer Immunology Center and academician of the National Academy of Sciences, published a paper in Science to clarify the function of CD8a protein on killer CD8+ T cells in peripheral lymphoid organs in vivo [10].
The research group used CRISPR-Cas9 technology to design drug-induced conditional CD8a gene knockout mice
(tamoxifen).
In the absence of drug (tamoxifen)-induced conditions, there was no difference between this conditional CD8a knockout mouse and wild-type normal mice, killer CD8+ T cells can develop normally and be positively selected in the thymus, and peripheral lymphoid organs are full of killer CD8+ T cells
.
Next, the group isolated CD8+ T cells from the peripheral lymphoid organs of conditioned CD8a knockout mice, and then transferred adoptively to wild-type mice, and drug (tamoxifen) injection recipient mice specifically knocked out the CD8a gene
on adoptively transferred CD8+ T cells.
Using this system, the function
of the CD8a gene on killer CD8+ T cells in vivo can be specifically studied.
Their study found that drug-induced conditional knockout of CD8a on perimeter-killing CD8+ T cells activates naïve or memory-killing CD8+ T cells while reducing the survival of naïve or memory CD8+ T cells, and further research suggests that the reduction of T cells caused by CD8a deletion may be programmed apoptosis
caused by T cell activation.
It is worth mentioning that the authors examined the molecules downstream of the TCR signaling pathway and found that the TCR signaling of CD8–/– T cells is weakened, so cell activation caused by CD8a deletion is not mediated by the TCR pathway
.
In order to confirm the discovery of drug-induced CD8a gene knockout, the author made a monoclonal antibody to CD8a, and found that the monoclonal antibody of CD8a injected into mice can also activate peripheral CD8+ T cells, in order to exclude the depletion effect of antibody Fc, the author sequenced the sequence of the monoclonal antibody of CD8a.
And by high-pressure injection method in mice expressing CD8a monoclonal antibody Fab fragment, it was found that Fab fragment can also activate naïve and memory CD8+ T cells and reduce the survival
of CD8+ T cells.
Next, the authors found the ligand PILRa for the human CD8a protein from a library containing about 6,000 membrane proteins, which can be confirmed by flow cytometry and ELISA, while CD8a-PILRa interactions are conserved
in mice 。 The authors found that either monoclonal antibodies or Fab fragments of CD8a could block CD8a-PILRa interactions, suggesting that their function in vivo may be due to blocking CD8a-PILRa interactions
.
PILRa is a membrane protein highly expressed on myeloid cells, and the authors also made a monoclonal antibody to PILRa to block CD8a-PILRa interactions
.
Injecting PILRa's blocking antibody in mice was found to also activate naïve and memory CD8+ T cells and reduce CD8+ cell survival
.
The authors also used CRISPR-Cas9 technology to produce PILRa knockout mice and found that there was no change in peripheral naïve or memory CD8+ T cells in young PILRa knockout mice, but at the age of one year, the peripheral memory CD8+ T cells of PILRa knockout mice decreased
significantly.
The authors hypothesize that an additional receptor of the PILRa molecule may have neutralized the inhibitory signal of PILRa-CD8a, causing PILRa knockout mice to develop a partial phenotype
until one year.
For nearly two decades, detailed studies by the immunology community on peripheral survival of naïve and memory CD8+ T cells have shown that MHC-I and IL-7 are responsible for the survival signal of naïve CD8+ T cells, while memory CD8+ T cells only need IL-7 and IL-15 to provide survival signals
。 This study shows that cellular homeostatic resting mediated by the PILRa–CD8a pathway is also an important mechanism for the survival of
naïve and memory CD8+ T cells.
Like many original articles, this article clarifies many questions while also opening up many new ones
.
For example, because secretory PILRa is not detectable in mouse serum, it shows that cell-cell interactions between myeloid cells-CD8+ T cells are important for maintaining homeostatic resting of CD8+ T cells.
For example, the paper found that CD8a deletion-induced T cell activation is not a TCR pathway to provide signals, so which pathway provides activation signals? Answering these new questions will further help us understand T cells
.
Academician Chen Lieping is the corresponding author of the article, and Dr.
Zheng Linghua is the first author
of the article.
First author Dr.
Linghua Zheng and second author Dr.
Xue Han have established two independent laboratories at The Ohio State University Pelotonia Immuno-Cancer Institute, which will continue to carry out cutting-edge exploration around basic immunology and immunotherapy (tumor immunity, autoimmune diseases) of T cells, and attach importance to clinical translational research, and welcome doctoral students, postdoctoral fellows, visiting students/scholars to join
.
Resume delivery (interested parties please send personal resume and other materials to): https://jinshuju.
net/f/ZqXwZt or scan the QR code Submit the original link of the resume
: https://doi.
org/10.
1126/science.
aaz8658
Platemaker: Eleven
References
1.
Miller, J.
F.
, Immunological Function of Thymus.
Lancet, 1961.
2(720): p.
748-&.
2.
Miller, J.
F.
A.
P.
, Effect of Neonatal Thymtomy on Immunological Responsiveness of Mouse.
Proceedings of the Royal Society Series B-Biological Sciences, 1962.
156(964): p.
415-+.
3.
Kisielow, P.
, et al.
, Ly Antigens as Markers for Functionally Distinct Subpopulations of Thymus-Derived Lymphocytes of Mouse.
Nature, 1975.
253(5488): p.
219-220.
4.
Shiku, H.
, et al.
, Subpopulations of Cytotoxic T Cells with Different Surface Phenotypes.
Proceedings of the American Association for Cancer Research, 1975.
16(Mar): p.
67-67.
5.
Cantor, H.
and E.
A.
Boyse, Functional Subclasses of T Lymphocytes Bearing Different Ly Antigens .
1.
Generation of Functionally Distinct T-Cell Subclasses Is a Differentiative Process Independent of Antigen.
Journal of Experimental Medicine, 1975.
141(6): p.
1376-1389.
6.
Cantor, H.
, et al.
, Characterization of Subpopulations of T-Lymphocytes .
1.
Separation and Functional Studies of Peripheral T-Cells Binding Different Amounts of Fluorescent Anti-Thy 1.
2 (Theta) Antibody Using a Fluorescence-Activated Cell Sorter (Facs).
Cellular Immunology, 1975.
15(1): p.
180-196.
7.
Norment, A.
M.
, et al.
, Cell-cell adhesion mediated by CD8 and MHC class I molecules.
Nature, 1988.
336(6194): p.
79-81.
8.
Veillette, A.
, et al.
, The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck.
Cell, 1988.
55(2): p.
301-8.
9.
Fung-Leung, W.
P.
, et al.
, CD8 is needed for development of cytotoxic T cells but not helper T cells.
Cell, 1991.
65(3): p.
443-9.
10.
Zheng, L.
, et al.
, The CD8alpha-PILRalpha interaction maintains CD8(+) T cell quiescence.
Science, 2022.
376(6596): p.
996-1001.
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