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Blood, 15 July 2004, Vol. 104, No. 2, pp. 478-486.
Prepublished online as a Blood First Edition Paper on March 25, 2004; DOI 10.1182/blood-2003-12-4395.
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IMMUNOBIOLOGY
Peripheral CD4+CD8+ T cells are differentiated effector memory cells with antiviral functions
Michelina Nascimbeni,
Eui-Cheol Shin,
Luis Chiriboga,
David E. Kleiner, and
Barbara Rehermann
From the Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, MD; Department of Pathology, Bellevue Hospital, New York University (NYU) School of Medicine, New York, NY; and Laboratory of Pathology, National Cancer Institute (NCI), NIH, DHHS, Bethesda, MD.
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. (Blood. 2004;104:478-486)
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