Cigarette smoke-primed citrullinated HLA-DR4 T cell reactivity is modulated by γδ-T cells
Authors' conclusion
These findings reveal a selective impact of CS on pulmonary T cell subsets and suggest that γδ T cells act as gatekeepers of HLA-DR4-mediated autoimmune responses in RA pathogenesis. They also highlight a potential 2-hit model involving IL-23 in driving T cell-mediated arthritis.
Study context
- Population
- Patients with early SE+ rheumatoid arthritis (RA) and HLA-DR4 transgenic mice
- Comparison
- Cigarette smoke exposure or Cit-ENOL immunisation vs unexposed, and γδ-T cell-deficient vs γδ-T cell-sufficient HLA-DR4 mice
- Outcome
- CD4+ T cell reactivity to citrullinated antigens (MHC-II tetramer) and arthritis development
Methodological detailshuman and HLA-DR4 transgenic mouse experiments, MHC-II tetramer detection
- Human and HLA-DR4 transgenic mouse experiments
- MHC-II tetramer detection
Main finding
As reported in the abstract
CS, HLA-DR4 and T cell responses to citrullinated antigens
- Cigarette smoke (CS) exposure enhanced T cell reactivity to citrullinated peptides, including Cit-ENOL, in the lungs of both patients and mice
- Cit-ENOL T cells, induced by CS or immunisation, did not directly trigger arthritis development
- IL-23 overexpression unleashed arthritogenic potential of Cit-ENOL T cells in immunised HLA-DR4 mice
- CS exposure and Cit-ENOL immunisation led to γδ-T cell activation strongly correlating with Cit-ENOL T cell responses
- γδ-T cell-deficient HLA-DR4 mice exhibited an aggravated arthritis phenotype, mirrored by altered functional Cit-ENOL T cell responses
Original publication
Cigarette smoke-primed citrullinated HLA-DR4 T cell reactivity is modulated by γδ-T cells. Ann Rheum Dis. Published 24 November 2025. doi:10.
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