Functional suppression by FoxP3+CD4+CD25(high) regulatory T cells during acute hepatitis C virus infection.
BACKGROUND
Infection with hepatitis C virus (HCV) is characterized by impairment of viral effector T cell responses and a high propensity for viral persistence. Previous studies have demonstrated that chronic HCV infection is associated with an increased frequency of regulatory T (T(reg)) cells, compared with that in persons whose infection resolved and in healthy persons. However, all patients in prior analyses had exposures in the distant past, precluding the ability to determine whether T(reg) cells play a causal role in establishing persistence during the earliest stages of infection or whether they are expanded because of viral persistence.


METHODS
For the first time, we longitudinally analyzed T(reg) cells in patients with acute HCV infection (n = 27). We used a multiparameter approach, including fluorescence-activated cell sorting analysis of cell-surface and intracellular antigens, coculture experiments with highly purified CD4(+)CD25(high) regulatory and CD4(+)CD25(-) responder cell populations, and multiplex analysis of secreted cytokines.


RESULTS
Forkhead transcription factor 3 (FoxP3) expression and T(reg) cell suppression were greater in patients with acute HCV infection than in healthy control subjects but were not different at the first time point among patients who subsequently developed persistence or resolved HCV infection spontaneously; however, 6 months later, the resolution of disease was associated with a relative loss of functional suppression.


CONCLUSIONS
Collectively, these data indicate that patients with acute HCV infection who develop chronicity versus spontaneous resolution exhibit temporal changes in T(reg) cell function. It is possible that repetitive viral antigenic stimulation alters the function of T(reg) cells over time.
Smyk-Pearson
Susan
S
Division of Gastroenterology and Hepatology, Hepatitis C Center, University of Colorado Health Sciences Center, GI Division, 4200 E. 9th Ave., B-158, Denver, CO 80262, USA.
Golden-Mason
Lucy
L
Klarquist
Jared
J
Burton
James R
JR
Tester
Ian A
IA
Wang
Chia C
CC
Culbertson
Nicole
N
Vandenbark
Arthur A
AA
Rosen
Hugo R
HR
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D051927:CD24 Antigen / Q000276:immunology; D016022:Case-Control Studies; D005260:Female; D015241:Fibrinogens, Abnormal; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D007111:Immunity, Cellular; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000276:immunology* / Q000821:virology*; D014766:Viremia
D051927:CD24 Antigen; C418974:FOXP3 protein, human; D015241:Fibrinogens, Abnormal; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; C433931:fibrinogen Longmont