Oscillating CD8(+) T cell effector functions after antigen recognition in the liver.
When hepatitis B virus (HBV)-specific CD8(+) cytotoxic T lymphocytes (CTLs) are adoptively transferred into HBV transgenic mice, they enter the liver, recognize antigen, secrete interferon gamma (IFNgamma), inhibit viral replication, and kill their target cells, causing hepatitis. In the current study, we examined the impact of antigen recognition on the evolution of the activation phenotype, antiviral effector functions, expansion and contraction kinetics, and compartmentalization of the transferred CTLs. The results reveal that noncytolytic and cytolytic effector functions and expansion-contraction kinetics of the CTLs are regulated asynchronously and in an oscillatory manner as a consequence of antigen recognition in the liver and in association with PD-1 upregulation. We suggest that such oscillations maximize viral clearance and minimize tissue injury during HBV infection and that poor coordination of these events could lead to viral persistence and chronic liver disease.
Isogawa
Masanori
M
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Furuichi
Yoshihiro
Y
Chisari
Francis V
FV
D019264:Adoptive Transfer; D000818:Animals; D053804:Granzymes; D006509:Hepatitis B / Q000276:immunology*; D006514:Hepatitis B Surface Antigens / Q000276:immunology*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012697:Serine Endopeptidases / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology* / Q000637:transplantation; D014759:Viral Envelope Proteins / Q000032:analysis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D006514:Hepatitis B Surface Antigens; D011948:Receptors, Antigen, T-Cell; D014759:Viral Envelope Proteins; C114312:middle envelope protein, Hepatitis B virus; D007371:Interferon-gamma; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases