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 plays 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 to 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 PBMC 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.