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Two Clocks Tell T Cells When Their Time’s Up

An Australian research team has revealed that the immune cells that fight infections in our body are under the control of two internal “clocks”, upending previous theories on how immune responses are regulated.

The team at the Walter and Eliza Hall Institute discovered that during an immune response the clocks allocate a certain amount of time in which the cells can divide, and also prescribe the immune cells’ lifespan. The finding sheds new light on how the body controls immune responses, and explains how cancers such as leukaemia and lymphoma may be caused by errors in this system.

Immune T cells are programmed to recognise different microbes. When this happens during an infection, the responding T cells become activated and increase in number by dividing. Tight controls on how many cells are formed and how long they survive ensure that the infection can be successfully fought and that excess immune cells are cleared so they don’t overwhelm the body.

“We had previously shown the number of cells a ‘parent’ T cell produces is tightly regulated,” said Dr Susanne Heinzel. “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,” she said. “Once this time is up, no more divisions can happen.

“Intriguingly, as well as being allocated a certain amount of time in which to divide, early in an infection we found T cells separately set how long they and their offspring live. After this time expires, the cells undergo apoptosis, a form of cell suicide,” Heinzel said.

Co-author of the Nature Immunology report, Prof Phil Hodgkin, said the team built on their discovery of the two-clock system by pinpointing a protein called Myc that acts as the cell division clock. “At the start of an immune response, responding T cells are allocated a certain amount of Myc,” he 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.

“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,” he said.

Heinzel said the research provided new insights into how complex immune responses are controlled, and the fine balance between normal cell division and cancerous cell growth. “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,” she 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 said.