PD-1-PD-L1 pathway impairs T(h)1 immune response in the late stage of infection with Mycobacterium bovis bacillus Calmette-Guérin.
A major concern still prevails as to the reason why various mycobacteria are able to persist within infected host in which protective immunity is generated. To address this question, we monitored the generation of protective T cells during infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG). CD4(+) T cells obtained 3 weeks after infection conferred protection against Mycobacterium tuberculosis challenge and produced IFN-γ and tumor necrosis factor (TNF)-α upon antigen stimulation. However, these abilities were decreased after 6 weeks of infection even though BCG was not thoroughly eliminated from the host. We analyzed the expression of ligands for the CD28/CTLA-4 family receptors on antigen-presenting cells and found that the expression of PD-L1, a ligand for programmed cell death-1 (PD-1), was up-regulated later than 3 weeks of infection. We also found that bacterial numbers in the spleen of PD-1-deficient mice were significantly reduced compared with wild-type mice at 6 and 12 weeks after BCG infection. Furthermore, CD4(+) T cells of PD-1-deficient mice showed a higher ability to confer protection and produce IFN-γ and TNF-α even at 12 weeks after infection. These results indicate that the PD-1-PD-L1 pathway impairs T(h)1 immunity in the late stage of BCG infection, thereby facilitating the bacterial persistence in the host.
Department of Microbiology, Kyoto University Graduate School of Medicine, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Shunsuke
S
Sakai
Ikuo
I
Kawamura
Taku
T
Okazaki
Kohsuke
K
Tsuchiya
Ryousuke
R
Uchiyama
Masao
M
Mitsuyama
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism*; D060890:B7-H1 Antigen; D001500:BCG Vaccine / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D008168:Lung / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology*; D010455:Peptides / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor; D013154:Spleen / Q000382:microbiology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001500:BCG Vaccine; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma