CD8+ regulatory T cells, and not CD4+ T cells, dominate suppressive phenotype and function after in vitro live Mycobacterium bovis-BCG activation of human cells.
Mycobacterium bovis bacillus Calmette-Guérin (M. bovis BCG), the only currently available vaccine against tuberculosis, has been reported to induce regulatory T cells in humans. The activity of regulatory T cells may not only dampen immunogenicity and protective efficacy of tuberculosis-vaccines, but also hamper diagnosis of infection of tuberculosis, when using immune (e.g. IFNγ-release) assays. Still, in settings of infectious diseases and vaccination, most studies have focused on CD4+ regulatory T cells, and not CD8+ regulatory T-cells. Here, we present a comparative analysis of the suppressive phenotype and function of CD4+ versus CD8+ T cells after in vitro live BCG activation of human cells. Moreover, as BCG is administered as a (partly) live vaccine, we also compared the ability of live versus heatkilled BCG in activating CD4+ and CD8+ regulatory T cell responses. BCG-activated CD8+ T cells consistently expressed higher levels of regulatory T cell markers, and after live BCG activation, density and (co-)expression of markers were significantly higher, compared to CD4+ T cells. Furthermore, selection on CD25-expression after live BCG activation enriched for CD8+ T cells, and selection on co-expression of markers further increased CD8+ enrichment. Ultimately, only T cells activated by live BCG were functionally suppressive and this suppressive activity resided predominantly in the CD8+ T cell compartment. These data highlight the important contribution of live BCG-activated CD8+ Treg cells to immune regulation and emphasize their possible negative impact on immunity and protection against tuberculosis, following BCG vaccination.
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Mardi C
MC
Boer
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Krista E
KE
van Meijgaarden
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Simone A
SA
Joosten
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Tom H M
TH
Ottenhoff
D000954:Antigens, Surface / Q000378:metabolism; D001500:BCG Vaccine / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D056747:Immunomodulation; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology*; D009163:Mycobacterium bovis / Q000276:immunology*; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D000954:Antigens, Surface; D001500:BCG Vaccine