Age-associated cytotoxic CD4+ T-cells shift hematopoiesis toward the myeloid lineage; CCR5 blockade improved outcomes in old mice

In old mice, CD4 T-cells with a cytotoxic program shift hematopoiesis toward neutrophil production

In an article published on August 26, researchers traced a pathway in mice from age-associated CD4 T-cells to a shift in hematopoiesis. These cells secrete CCL5, which acts through the CCR5 receptor on blood cell progenitors and increases production of cells from the myeloid lineage, including neutrophils. A month-long course of maraviroc, a drug that blocks CCR5, altered bone marrow and blood measurements as well as physical test performance in 23-month-old mice.

Bone marrow continuously produces blood cells. With age, the bone marrow of mice increasingly directs progenitors toward the myeloid lineage, which gives rise to neutrophils and monocytes, while the number of cells that produce lymphocytes declines. The authors found that CD4 T-cells, immune cells that coordinate the immune response, accumulate in old bone marrow. A subset of these cells acquired a cytotoxic program and secreted CCL5, a signaling molecule that acts on nearby cells.

To test whether these cells cause the shift, the researchers transferred CD4 T-cells from old or young mice into young mice that lacked their own T- and B-cells. Seven days later, the proportions of early myeloid progenitors and neutrophils in the bone marrow were higher in animals that had received cells from old donors. This transfer showed that age-associated properties of T-cells can alter blood cell production.

The authors then identified which cells receive the signal. Progenitors with and without the CCR5 receptor developed simultaneously in the same animal, where they shared the same environment and were exposed to the same transferred T-cells. After cells from old mice were transferred, the proportion of early myeloid progenitors increased only among cells with CCR5. In cell culture, an antibody against CCL5 prevented the increased production of these cells. Together, these experiments connected the source of the signal, CCL5, and the receptor on the receiving cell in a single causal pathway.

Some of the authors of the current article had previously studied a related mechanism. In a 2020 study, they impaired mitochondrial function in mouse T-cells and produced chronic inflammation accompanied by age-associated abnormalities in several organs. In the new study, repeated stimulation of T-cells impaired mitochondrial function and increased CCL5 production. Disabling the intracellular signaling protein STING reduced CCL5 production while leaving the cytotoxic program intact. These experiments allowed the authors to test the pathway from repeated T-cell stimulation to CCL5 production.

Finally, 23-month-old mice received daily maraviroc, a drug that blocks CCR5, for one month. The proportions of early myeloid progenitors and blood neutrophils declined, and fewer neutrophils entered the lungs and liver. The neutrophil-to-lymphocyte ratio also decreased. Grip strength and the time that the mice remained on a rotating rod increased in physical tests.

In people older than 110 years, CD4 T-cells with a cytotoxic program form large clones in the blood. The new study in old mice shows how such cells in the bone marrow shift hematopoiesis toward the myeloid lineage through CCL5 and CCR5.