Heterogeneous landscape of CD4 T cells develops with age and comprises unique subsets with distinct phenotypic properties

Introduction:

One of the key hallmark of aging is the deterioration of the immune system, a phenomenon which prone to increased susceptibility of elderly individuals to infection, chronic inflammatory disorders and vaccination failure. A significant change observed in aging is a dynamic variation in the composition and functionality of CD4 T cells along with the accumulation of dysregulated T cells. However, a detailed, high resolution, characterization of CD4 T-cell phenotypes, which may explain these dysregulated functional properties, is lacking.

Materials and methods:

We used scRNA-seq and flow cytometry data, together with functional assays which allowed us in-depth characterization of CD4 T-cell subsets in aging. We profiled thousands of CD4 T cells obtained from young and old mice in order to explore the differences in population structure at different stages of aging.

Results and discussion:

We found that the cell composition of CD4 T-cell subsets in old mice is markedly different from young mice. Three cell populations were identified in this study: exhausted, MHCII-restricted cytotoxic, and activated regulatory (aTregs) CD4 T cells. These subsets appear rarely in young mice and gradually accumulate in old mice, reaching about 30% of the CD4 T-cell lineage. Moreover, the cytotoxic CD4 T cells and aTregs presented high variability at different stages of aging.

Conclusion:

In the current study, we aimed to comprehensively describe how the CD4 T-cell compartment is sculptured during the process of aging. We identified a gradual reorganization of the CD4 T-cell compartment, where regulatory, exhausted and cytotoxic phenotypes co-emerge with age. These findings provide a thorough view of the dynamic reorganization of the CD4 T-cell milieu with age and illuminate dominant cell subsets associated with declined immunity and chronic inflammation.