Immune cells triggered to fight an infection have two distinct and controlling internal clocks — one determines the amount of time such a cell has to divide, and the other determines how long the cell and its offspring have to live.
The findings shed light not only on how the body controls immune responses, but may explain how particular mutations that affect these clocks can aid certain hematological cancers, like leukemia and lymphoma.
The study, published in Nature Immunology, is titled, “A Myc-dependent division timer complements a cell-death timer to regulate T cell and B cell responses.”
When the immune system recognizes a foreign pathogen, such as bacteria, a virus, or cancer cells, immune T-cells are activated to fight that infection. This involves the rapid replication of subsets of T-cells that recognize and target proteins at the surface of those pathogens.
Although researchers know that this process is tightly regulated, making sure that both the infection is cleared and the immune cells themselves are cleared from the body, the mechanisms in such regulation are not fully understood.
Researchers at the Walter and Eliza Hall Institute in Australia studied the mechanisms involved in the control of immune cell division and clearance. They believed that cell division was controlled by limiting the number of divisions a T-cell could undergo, but their findings proved otherwise; instead of limiting the number of divisions, each cell, they found, has a limited time to divide.
“We had previously shown the number of cells a ‘parent’ T cell produces is tightly regulated,” Dr. Susanne Heinzel, who led the study together with Professor Phil Hodgkin, said in a press release. “The suspicion was the T cell ‘knows’ how many times it can divide. We were stunned to find this wasn’t the case — the T cell is given an amount of time in which it can divide, like a clock running. Once this time is up, no more divisions can happen.”
The researchers found that this clock was controlled by the amount of Myc, a protein that is mutated in several leukemias and lymphomas.
“At the start of an immune response, responding T cells are allocated a certain amount of Myc,” Heinzel said. “This diminishes over time, and once the cell runs out of Myc, time’s up and division stops. The more Myc there is, the more time the cells have to divide.”
And they found a molecular clock that determined the lifespan of immune T-cells. When the time expired, the immune cells entered apoptosis, which is a form of cell death.
“We also showed the lifespan clock is controlled by a protein called Bcl-2 — when this time runs out the cells die, whether or not they’ve come to the end of their division clock,” Heinzel said.
The findings continue to highlight the complexity of immune responses, and may provide fresh insights into how hematological malignancies develop.
“The two clocks are an elegant way that our body governs how many responder cells are produced in an immune response, and how long they are retained,” Heinzel said. “Small changes in each clock combined to substantially alter immune cell numbers.
“It has been known for many years that excess Myc and Bcl-2 are important contributors to cancer formation. Our findings explain how a small series of mutation-driven changes in healthy immune responses could lead to immune cell cancers such as leukaemia and lymphoma,” she added.
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