Loss of IL-7 receptor alpha-chain (CD127) expression in acute HCV infection associated with viral persistence.
Interleukin-7 (IL-7) is required for the establishment and maintenance of memory CD4(+) and CD8(+) T lymphocytes, and cells lacking IL-7Ralpha (CD127) demonstrate impaired IL-2 secretion and have a short life-span. Chronic HCV is characterized by T cells that are functionally impaired and exhibit an immature phenotype. To investigate the potential role of IL-7/IL-7Ralpha in the outcome of HCV infection, we used multiparameter flow cytometry to characterize patients with acute infection (n = 24), long-term chronic infection (12) and normal subjects (13). HCV infection per se resulted in downregulation of CD127 on total CD4(+) and CD8(+) T lymphocytes as compared to normal controls. Total expression was lowest in those patients who subsequently developed persistence and intermediate in those patients with acute-resolving infection. This reduction affected both naïve and effector/memory T cells. CD127 correlated phenotypically with upregulation of chemokine receptors CCR7 and CXCR4, expression of the anti-apoptotic molecule B cell leukemia/lymphoma 2 (Bcl-2), and enhanced IL-2 production. In six HLA A2-positive patients, we longitudinally tracked tetramer responses to HCV and CMV epitopes; at baseline, reflecting the expression of CD127 on whole T cell populations, viral-specific CTLs in patients who became chronic demonstrated lower CD127. In conclusion, CD127 is a useful marker of functional CD4(+) and CD8(+) T cells and its expression correlates with virologic outcome of acute HCV. These data provide a mechanistic basis for the observation that CTLs generated in early infection rapidly decline as chronicity is established; CD127 expression should be considered in the design of novel immunotherapeutic approaches.
Golden-Mason
Lucy
L
Division of Gastroenterology & Hepatology, Hepatitis C Center, and Integrated Program in Immunology, University of Colorado Health Sciences Center & National Jewish Hospital, Denver, CO, USA.
Burton
James R
JR
Castelblanco
Nicole
N
Klarquist
Jared
J
Benlloch
Salvador
S
Wang
Chia
C
Rosen
Hugo R
HR
D000208:Acute Disease; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D000939:Epitopes; D005260:Female; D005434:Flow Cytometry; D016174:Hepacivirus / Q000276:immunology; D006526:Hepatitis C / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D012367:RNA, Viral / Q000302:isolation & purification; D020395:Receptors, Interleukin-7 / Q000276:immunology / Q000378:metabolism*
D000939:Epitopes; D053699:Interleukin-7 Receptor alpha Subunit; D012367:RNA, Viral; D020395:Receptors, Interleukin-7