PD-1 modulates regulatory T cells and suppresses T-cell responses in HCV-associated lymphoma.
T regulatory (T(R)) cells suppress T-cell responses that are critical in the development of chronic viral infection and associated malignancies. Programmed death-1 (PD-1) also has a pivotal role in regulation of T-cell functions during chronic viral infection. To examine the role of PD-1 pathway in regulating T(R)-cell functions that inhibit T-cell responses during virus-associated malignancy, T(R) cells were investigated in the setting of hepatitis C virus-associated lymphoma (HCV-L), non-HCV-associated lymphoma (non-HCV-L), HCV infection alone and healthy subjects (HS). Relatively high numbers of CD4(+)CD25(+) and CD8(+)CD25(+) T(R) cells, as well as high levels of PD-1 expressions on these T(R) cells were found in the peripheral blood of subjects with HCV-L compared with those from non-HCV-L or HCV alone or HS. T(R) cells from the HCV-L subjects were capable of suppressing the autogeneic lymphocyte response, and depletion of T(R) cells in peripheral blood mononuclear cells from HCV-L improved T-cell proliferation. Additionally, the suppressed T-cell activation and proliferation in HCV-L was partially restored by blocking the PD-1 pathway ex vivo, resulting in both a reduction in T(R)-cell number and the ability of T(R) to suppress the activity of effector T cells. This study suggests that the PD-1 pathway is involved in regulating T(R) cells that suppress T-cell functions in the setting of HCV-associated B-cell lymphoma.
Division of Infectious Diseases, Department of Internal Medicine, East Tennessee State University College of Medicine, Box 70622, Johnson City, TN 37614, USA.
Lei
L
Ni
Cheng J
CJ
Ma
Ying
Y
Zhang
Subhadra
S
Nandakumar
Chun L
CL
Zhang
Xiao Y
XY
Wu
Thomas
T
Borthwick
Agnes
A
Hamati
Xin Y
XY
Chen
Uday
U
Kumaraguru
Jonathan P
JP
Moorman
Zhi Q
ZQ
Yao
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D019698:Hepatitis C, Chronic / Q000150:complications / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008223:Lymphoma / Q000150:complications / Q000276:immunology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor