Annals of the rheumatic diseases · 2025
Cigarette smoke-primed citrullinated HLA-DR4 T cell reactivity is modulated by γδ-T cells.
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Jarlborg Matthias, Decruy Tine, Manuello Teddy, Coudenys Julie, Van der Cruyssen Renée, Malfait Thomas L A, Meuris Leander, Maes Tania, Bracke Ken R, van der Woude Diane, Athanasiadou Aegli, Wittoek Ruth, Jacques Peggy, Elewaut Dirk, Venken Koen
Аннотация
OBJECTIVES: Cigarette smoke (CS) increases the risk of seropositive rheumatoid arthritis (RA), particularly in individuals carrying HLA-DR4 (Human Leukocyte Antigen-DR4) shared epitope (SE) alleles, though the underlying mechanisms remain unclear. This study aimed to investigate the interaction between these 2 key risk factors-CS and HLA-DR4-and their effect on T cell responses to citrullinated antigens in early RA and in HLA-DR4 transgenic mice.
METHODS: Major histocompatibility complex (MHC)-II tetramer technology was used to detect CD4+ T cells specific for citrullinated antigens in patients with early SE+ RA and in HLA-DR4 transgenic mice. Mice were exposed to CS or immunised with citrullinated α-enolase (Cit-ENOL) to assess T cell responses. Systemic interleukin (IL)-23 overexpression was induced by hydrodynamic injection of IL-23-enhanced episomal vector.
RESULTS: CS exposure enhanced T cell reactivity to citrullinated peptides, including Cit-ENOL, in the lungs of both patients and mice. While Cit-ENOL T cells, either induced by CS or immunisation, did not directly trigger arthritis development, IL-23 overexpression unleashed their arthritogenic potential in immunised HLA-DR4 mice. Interestingly, CS exposure and Cit-ENOL immunisation led to γδ-T cell activation strongly correlating with Cit-ENOL T cell responses. Furthermore, γδ-T cell-deficient HLA-DR4 mice exhibited an aggravated arthritis phenotype, mirrored by altered functional Cit-ENOL T cell responses.
CONCLUSIONS: 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.
METHODS: Major histocompatibility complex (MHC)-II tetramer technology was used to detect CD4+ T cells specific for citrullinated antigens in patients with early SE+ RA and in HLA-DR4 transgenic mice. Mice were exposed to CS or immunised with citrullinated α-enolase (Cit-ENOL) to assess T cell responses. Systemic interleukin (IL)-23 overexpression was induced by hydrodynamic injection of IL-23-enhanced episomal vector.
RESULTS: CS exposure enhanced T cell reactivity to citrullinated peptides, including Cit-ENOL, in the lungs of both patients and mice. While Cit-ENOL T cells, either induced by CS or immunisation, did not directly trigger arthritis development, IL-23 overexpression unleashed their arthritogenic potential in immunised HLA-DR4 mice. Interestingly, CS exposure and Cit-ENOL immunisation led to γδ-T cell activation strongly correlating with Cit-ENOL T cell responses. Furthermore, γδ-T cell-deficient HLA-DR4 mice exhibited an aggravated arthritis phenotype, mirrored by altered functional Cit-ENOL T cell responses.
CONCLUSIONS: 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.