Cell paper interpretation! The new findings upend traditional perceptions of killer T-cells and help develop CAR-T cells that better target solid tumors

December 12, 2020 // --- Immune cells called "lethal T cells", also known as cytotoxic or soluble CD8 T cells.
a new study, researchers at the University of Pennsylvania's Perelman School of Medicine found that lethal T cells usually remain in the blood and do not enter organs and other tissues.
results were published online December 10, 2020 in the journal Cell under the title "The Identity of Human Tissue-Emigrant CD8 plus T Cells."
from Cell, 2020, doi:10.1016/j.cell.2020.11.019.
The discovery may help solve many of the challenges of immunology, including medical mysteries such as why recently developed cancer treatments using genetically modified lethal T-cells do not work well against solid tumors, and why HIV, the AIDS-related virus that is thought to be very vulnerable to killer T-cells, seems to be able to escape these immune cells indefinitely by hiding out of the blood.
, co-author of the paper and professor of microbiology at the University of Pennsylvania's Perelman School of Medicine, said, "This finding tells us that killer T cells don't usually migrate out of the bloodstream."
now that we know this, we can begin to design treatments that make better use of these powerful cells.
" lethal T-cells have long been considered the main force of the immune system.
each killer T cell carries an antibody-like subject that can identify specific targets.
Killer T cells are called "cytotoxic" or "cell-soluble" CD8 T cells because they have special molecular weapons that directly attack and destroy other cells that show the targets they identify, such as virally infected cells and even cancer cells.
traditional immunologists believe that killer T-cells more or less circulate from the blood to tissue and then into the bloodstream, destroying targets they identify anywhere in the body at any time.
, however, this view is based mainly on the study of animals.
study of human T-cells is mostly limited to sampling these immune cells from the blood.
the new study, Betts and his team were able to take a broader look at the movement of T-cells in the body by analyzing blood and lymphatic fluid samples from humans and macaques.
is a white, watery liquid that flows out of various tissues and organs of the body and enters the bloodstream through a network of blood vessels and lymph nodes called the lymphatic system.
T-cells and other immune cells that enter tissue from the blood flow back into the bloodstream through this lymphatic pathway.
scientists took samples from --- thoracic duct, part of the lymphatic network ---, and most of the lymphatic fluid flowed through the thoracic catheter.
in this way, the researchers were able to catalog the detailed molecular characteristics of T cells sampled from thoracic catheter lymphatic fluid and compare them with T cells collected from the blood of the same subject.
among the many findings of the study, the most striking is that CD8 T cells present in lymphatic fluid ---d8 T cells that migrate in organs and other tissues other than blood--- are not usually classic killer T cells that are present in the blood.
In fact, all CD8 T cells in lymphatic fluid do not have the ability to directly kill cells, but instead appear to have the ability to produce chemicals called immune cytokines, which summon other components of the immune system.
These non-cytotoxic CD8 T cells also appear to be able to identify the same targets as killer T cells in the blood, suggesting that the two groups of CD8 T cells developed from the same primary cells and have different but complementary effects in fighting the same pathogens.
the researchers say the findings are significant for basic immunology because they expand understanding of how these important immune cells function and overturn the traditional hypothesis that killer T cells circulate from the blood to tissues and then back into the bloodstream.
, for example, the role of non-cytotoxic CD8 T cells in the migration of tissues other than blood flow, these findings seem to have important medical significance.
one of the implications relates to CAR-T cell therapy for cancer, which uses lethal T-cells from patients to genetically adapt them to kill cancer cells.
CAR-T cell therapy has been remarkably successful in treating leukemia and other blood-borne cancers, so far there has been little success in treating solid tumors in organs and tissues other than blood.
new findings from the study suggest that CAR-T cells could be further genetically modified to take risks outside the bloodstream, effectively attacking solid tumors.
beat is a tumor that enters the bloodstream where cytotoxic T cells cannot enter the lungs, intestines, breasts, etc. because they don't have the right properties to do so," Betts said.
, according to Betts, these new findings may help explain why viruses such as HIV can evade the immune system indefinitely while infecting organs and tissues other than blood.
At the same time, these findings may lead to better ways to prevent the inappropriate migration of killer T-cells beyond the bloodstream, causing harm to the body, such as immune rejection of transplanted organs, and in some autoimmune diseases caused by inappropriate T-cell activity, such as multiple sclerosis, type 1 diabetes, and rheumatoid arthritis.
Betts and his colleagues are now conducting further follow-up studies in several directions.
in a project, they will look at how to remodel CAR-T cells to better migrate to solid tumors.
in another project, they will try to find out how mature CD8 T cells become hemogenic cytotoxic CD8 T cells or non-cytotoxic CD8 T cells that migrate in tissues.
(Bioon.com) :1. Marcus Buggert et al. The Identity of Human Tissue-Emigrant CD8+ T Cells. Cell, 2020, doi:10.1016/j.cell.2020.11.019.2.Researchers find that CD8 T cells remain in the bloodstream, do not enter organs and other tissues。