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.