Peripheral CD4(+)CD8(+) T cells are differentiated effector memory cells with antiviral functions.
Although an increased frequency of CD4(+)CD8(+) T cells has been observed in the peripheral blood during viral infections, their role, function, and biologic significance are still poorly understood. Here we demonstrate that the circulating CD4(+)CD8(+) T-cell population contains mature effector memory lymphocytes specific for antigens of multiple past, latent, and high-level persistent viral infections. Upon in vitro antigenic challenge, a higher frequency of CD4(+)CD8(+) than single-positive cells displayed a T helper 1/T cytotoxic 1 (Th1/Tc1) cytokine profile and proliferated. Ex vivo, more double-positive than single-positive cells exhibited a differentiated phenotype. Accordingly, their lower T-cell receptor excision circles (TREC) content and shorter telomeres proved they had divided more frequently than single-positive cells. Consistent with expression of the tissue-homing marker CXCR3, CD4(+)CD8(+) T cells were demonstrated in situ at the site of persistent viral infection (ie, in the liver during chronic hepatitis C). Finally, a prospective analysis of hepatitis C virus (HCV) infection in a chimpanzee, the only animal model for HCV infection, showed a close correlation between the frequency of activated CD4(+)CD8(+) T cells and viral kinetics. Collectively, these findings demonstrate that peripheral CD4(+)CD8(+) T cells take part in the adaptive immune response against infectious pathogens and broaden the perception of the T-cell populations involved in antiviral immune responses.
Nascimbeni
Michelina
M
Liver Diseases Section, DDB, NIDDK, National Institutes of Health, DHHS 10 Center Drive, Bldg 10, Room 9B16, Bethesda, MD 20892-1800, USA.
Shin
Eui-Cheol
EC
Chiriboga
Luis
L
Kleiner
David E
DE
Rehermann
Barbara
B
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000821:virology*; D000939:Epitopes; D015329:Gene Rearrangement, T-Lymphocyte; D019698:Hepatitis C, Chronic / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D016130:Immunophenotyping; D002679:Pan troglodytes; D016615:Telomere / Q000276:immunology
D000939:Epitopes