Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: the role of the virus.
In a companion study, we showed a dichotomy between the expansion of central memory (CCR7(+)) hepatitis C virus (HCV)-specific CTL and the incomplete memory effector differentiation in patients with acute HCV infection. Indeed, effector cells were unable to perform immediate functions, despite expressing the tissue-homing phenotype of effector memory cells (CCR7(-); semi-effectors). However, since they promptly differentiated into full-effectors upon IL-2 contact, we suggested that the inhibitory effect by environmental (possibly viral) factors on IL-2 production may have a pivotal role in generating the large population of semi-effector CCR7(-)/IFN-gamma(-) CTL. In accord with this view, we report here strong evidence in support of circulating HCVcore protein (HCVcore) playing a central role in inhibiting effector CTL differentiation, but not memory CTL expansion. The regulatory HCVcore effect is related to inhibition of the signal transduction pathway instrumental for IL-2 production, supporting the evidence that IL-2 was capable both of pushing semi-effector CTL to complete their effector cell program and of restoring the HCVcore-dependent inhibitory effect. Therefore, the strength of CTL activation is dependent on the balance between the threshold of stimulatory signals and the viral interference capacities provided during priming.
Accapezzato
Daniele
D
Fondazione Andrea Cesalpino and Dipartimento di Medicina Interna, Università degli Studi di Roma La Sapienza, Rome, Italy.
Francavilla
Vittorio
V
Rawson
Pisana
P
Cerino
Antonella
A
Cividini
Agostino
A
Mondelli
Mario U
MU
Barnaba
Vincenzo
V
D000208:Acute Disease; D000328:Adult; D000368:Aged; D002454:Cell Differentiation / Q000276:immunology*; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D014758:Viral Core Proteins / Q000276:immunology / Q000494:pharmacology
C515370:CCR7 protein, human; D007376:Interleukin-2; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D020929:Mitogen-Activated Protein Kinase Kinases