Augmented expression of programmed death‐1 in both neoplastic and non‐neoplastic CD4+ T‐cells in adult T‐cell leukemia/lymphoma

Abstract Adult T‐cell leukemia/lymphoma (ATL) is a CD4 + CD25 + T‐cell malignancy infected with human T‐cell leukemia virus type‐I (HTLV‐I). HTLV‐I infection causes the T‐cell dysfunction, which contributes to the immunodeficient state of the patients. Programmed death‐1 (PD‐1) can negatively regulate T‐cell response, when its ligand, PD‐L1 or PD‐L2 mainly expressed on antigen presenting cells, binds to this B7 family receptor. We investigated whether PD‐1 is expressed on CD4 + neoplastic (and/or non‐neoplastic) cells or CD8 + cytotoxic cells in peripheral blood mononuclear cells from 11 patients with ATL. By flow cytometry, we found that the levels of PD‐1 expression on both CD4 + CD25 + and CD4 + CD25 − T‐cell populations were increased in ATL patients compared to normal healthy volunteers, while PD‐1 levels on CD8 + T‐cells were comparable between the patients and normal subjects. In stimulation with anti‐CD3 antibody, the proliferation of PD‐1‐expressing T‐cells from ATL patients was weak when compared to that of PD‐1‐nonexpressing normal T‐cells. In addition to PD‐1, PD‐L1 was coexpressed on ATL cells in some patients, and PD‐L1 expression was enhanced by stimulation with anti‐CD3 antibody. Finally, the production of cytokines such as TNF‐α by ATL cells was restored by blockade of PD‐1/PD‐L1 interaction. These findings suggest that CD4 + T‐cells are the main PD‐1‐expressing cells rather than CD8 + T‐cells in ATL patients, and both neoplastic and normal CD4 + cells are exhausted as a result of PD‐1 expression, and additionally PD‐L1 expression on the neoplastic cell. © 2007 Wiley‐Liss, Inc.