Dynamics of pulmonary mucosal cytotoxic CD8 T-cells in people living with HIV under suppressive antiretroviral therapy

Respir Res. 2024 Jun 12;25(1):240. doi: 10.1186/s12931-024-02859-2.


Background: Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their smoking status. Cytotoxic CD8 T-cells are likely implicated in this phenomenon and may act as a double-edged sword. While being essential in viral infection control, their hyperactivation can also contribute to lung mucosal tissue damage. The effects of HIV and smoking on pulmonary mucosal CD8 T-cell dynamics has been a neglected area of research, which we address herein.

Methods: Bronchoalveolar lavage (BAL) fluid were obtained from ART-treated PLWH (median duration of supressed viral load: 9 years; smokers: n = 14; non-smokers: n = 21) and HIV-uninfected controls (smokers: n = 11; non-smokers: n = 20) without any respiratory symptoms or active infection. Lymphocytes were isolated and CD8 T-cell subsets and homing markers were characterized by multiparametric flow cytometry.

Results: Both smoking and HIV infection were independently associated with a significant increase in frequencies of total pulmonary mucosal CD8 T-cell. BAL CD8 T-cells were primarily CD69 + expressing CD103 and/or CD49a, at least one of the two granzymes (GzmA/GzmB), and little Perforin. Higher expression levels of CD103, CD69, and GzmB were observed in smokers versus non-smokers. The ex vivo phenotype of GzmA + and GzmB + cells revealed increased expression of CD103 and CXCR6 in smokers, while PLWH displayed elevated levels of CX3CR1 compared to controls.

Conclusion: Smoking and HIV could promote cytotoxic CD8 T-cell retention in small airways through different mechanisms. Smoking likely increases recruitment and retention of GzmB + CD8 Trm via CXCR6 and CD103. Heightened CX3CR1 expression could be associated with CD8 non-Trm recruitment from the periphery in PLWH.

Keywords: CD8 T-cells; HIV; Lung; People living with HIV (PLWH); Pulmonary immunity; Smoking; Tissue resident; Trm.

MeSH terms

  • Adult
  • Anti-HIV Agents / therapeutic use
  • Anti-Retroviral Agents / therapeutic use
  • Bronchoalveolar Lavage Fluid / immunology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Female
  • HIV Infections* / drug therapy
  • HIV Infections* / immunology
  • Humans
  • Lung / drug effects
  • Lung / immunology
  • Lung / metabolism
  • Male
  • Middle Aged
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / metabolism
  • Smoking / adverse effects
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism


  • Anti-Retroviral Agents
  • Anti-HIV Agents