Peculiar phenotypic and functional characteristics of pulmonary mucosal CD8 T-cells compared to peripheral blood
Peculiar phenotypic and functional characteristics of pulmonary mucosal CD8 T-cells compared to peripheral blood
Yulia Alexandrova1,2,3, Oussama Meziane1,2, Ron Olivenstein4, FranckDupuy1,Elaine Thomson1,2,3, Marianna Orlova1, Erwin Schurr1,5, Petronela Ancuta6,7, Nicolas Chomont6,7, Jerome Estaquier8, Nicole F. Bernard1,2, Cecilia T. Costiniuk1,2,9,and Mohammad-Ali Jenabian2,3,7
1Infectious
Diseases and Immunity in Global Health Program, Research Institute of McGill
University Health Centre, Montreal, QC, Canada
2Department
of Biological Sciences, Université du QuébecàMontréal,
Montreal, QC, Canada
3Department
of Microbiology and Immunology, McGill University, Montreal, QC, Canada
4Division
of Respirology, Department of Medicine, McGill University, Montreal, QC, Canada
5Department
of Human Genetics, McGill University, Montreal, QC, Canada
6Centre
de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, QC,
Canada
7Département
de microbiologie, infectiologie et immunologie, Université de Montréal,
Montreal, QC, Canada
8Centre Hospitalier
Universitaire (CHU) de Québec Research Center, Faculty of Medicine, Université
Laval, Quebec City,QC, Canad
9Division
of Infectious Diseases and Chronic Viral Illness Service, McGill University
Health Centre, Montreal, QC, Canada
Background:Airway mucosa is continuously exposed to various airborne stimuli which, in turn, affect lung mucosal immune cell physiology.CD8 T-cells play key immune functions via cytokine secretion and cytotoxicity towards virus-infected cells. Furthermore, HIV+ individuals have high burdens of pulmonary infections and lung cancers despite suppressive antiretroviral therapy (ART). We thus performed phenotypical and functional analyses ofpulmonary versus peripheral blood CD8 T-cells in ART-treated HIV+ and uninfected participants.
Methods:Bronchoalveolar lavage (BAL) fluid and matched blood were obtained from asymptomatic ART-treated HIV+ smokers (n=11) and non-smokers (n=15) and uninfected smokers (n=7) and non-smokers (n=10). CD8 T-cell subsets and phenotypes were assessed by flow cytometry. Perforin/granzyme-B content, degranulation (CD107a expression) and cytotoxicity against autologous Gag peptide-pulsed CD4 T-cells (Annexin-V+) following in vitro stimulation were assessed.
Results:In all groups, pulmonary CD8 T-cells were enriched in effector memory subsets compared to blood and displayed higher levels of activation (HLA-DR+) and exhaustion (PD1+) markers. Significant reductions in proportions of senescent pulmonary CD28-CD57+ CD8 T-cells were observed only in HIV+ smokers. Pulmonary CD8 T-cells showed lower perforin expression ex vivo compared to blood CD8 T-cells, with reduced granzyme-B expression only in HIV+ non-smokers. BAL CD8 T-cells showed significantly lower fold change in degranulation upon stimulation and lower CD4 killing capacity than blood CD8 T-cells.
Conclusion: Regardless of HIV status, pulmonary mucosal CD8 T-cells are more differentiated, activated and exhausted, with reduced killing-capacity in vitro than blood CD8 T-cells. Smoking alters CD8 dynamics in HIV individuals by reducing their immuno-senescence.
