Single-cell analyses identify dysfunctional CD16⁺ CD8 T cells in smokers.

Area of Science:

• Immunology
• Cell Biology
• Genomics

Background:

• Tobacco smoke exposure is a major risk factor for numerous diseases.
• Understanding smoking's impact on the immune system is crucial for public health.
• Specific immune cell alterations in smokers remain incompletely characterized.

Purpose of the Study:

• To identify specific immune cell populations altered by tobacco smoke exposure.
• To investigate the functional and differentiation state of these altered cells.
• To explore the relationship between smoking, immune aging, and T cell senescence.

Main Methods:

• Single-cell RNA sequencing of peripheral blood from smokers and nonsmokers.
• Mass cytometry to validate cell population frequencies.
• Pseudotime analysis to infer cell differentiation trajectories.
• DNA methylation analysis to assess biological aging and telomere length.

Main Results:

• A distinct subpopulation of CD16 (FCGR3A)-expressing Natural Killer (NK)-like CD8 T lymphocytes was identified and found to be increased in smokers.
• These NK-like CD8 T cells are highly differentiated, resembling effector memory re-expressing CD45RA (T_EMRA) cells.
• Smokers exhibited a bias toward differentiated CD8 T cells and a reduction in naive T cells, indicative of immune aging.
• Smoking dose correlated with accelerated biological aging and shorter telomere length, a marker of T cell senescence.

Conclusions:

• Smoking induces immune aging and T cell senescence, characterized by an increase in differentiated CD16+ CD8 T cells.
• This smoking-induced immune dysregulation may contribute to the pathogenesis of smoking-related diseases.
• The findings highlight a potential mechanism linking smoking to impaired immune function and increased disease susceptibility.