In aged mouse livers, T cells near CD44-positive hepatocytes, the organ's main cell type, show weaker activation of immune response genes

In aged mouse livers, T cells near CD44-positive hepatocytes, the organ's main cell type, show weaker activation of immune response genes

On August 13, the authors of an article in npj Aging compared young and aged male mice. They transferred identical young T cells into their livers and mapped the spatial organization of the tissue. In aged livers, these cells produced IFN-γ less often. T cells near CD44-positive hepatocytes also showed weaker expression of genes encoding immune signaling molecules. Knocking out Cd44 in hepatocytes reduced the hepatic IL-6/JAK/STAT3 signature.

The authors wanted to separate the effects of T-cell age from those of tissue age. They induced hepatocytes in young and aged mouse livers to produce the same antigen, a target recognized by T cells. They then transferred activated CD8 T cells from a young donor into both groups of animals.

Five days later, the numbers of transferred cells were similar in the two groups. After stimulation, T cells isolated from aged livers produced IFN-γ less often. IFN-γ is a signaling protein released by activated T cells.

Hepatocytes are the main functional cells of the liver. In aged male mice, the median proportion of CD44-positive hepatocytes increased from 1.09% to 2.95%. CD44 is a protein on the cell surface. Genes associated with the IL-6/JAK/STAT3 inflammatory signaling pathway were more active in this small population.

To examine this relationship within the tissue, the authors created spatial maps of liver sections. These maps show which genes are active in neighboring cells. T cells near CD44-positive hepatocytes showed weaker expression of cytokine and chemokine genes. Cytokines and chemokines are molecules that immune cells use to communicate.

“We observed local suppression of effector cytokines in T cells near CD44-positive hepatocytes, rather than uniform T-cell dysfunction throughout the aged liver,” the authors write.

In a separate experiment, the authors knocked out Cd44 in the hepatocytes of aged mice. Eight weeks later, the IL-6/JAK/STAT3 signature was reduced in RNA from the whole liver. In this mouse model, the age of the liver itself altered the response of otherwise identical young T cells. The spatial data pointed to small regions containing CD44-positive hepatocytes where the T-cell response program was weakened.