title: Naturally occurring PD-1+ memory phenotype CD8 T cells belong to nonconventional CD8 T cells and are cyclophosphamide-sensitive regulatory T cells.
abstract: CD8 T cells expressing memory markers exist in naive mice and are thought to be of heterogeneous origin. It was recently reported that among such memory-phenotype (MP) CD8 T cells in naive mice, those expressing programmed death-1 (PD-1) had immune regulatory activity, but their origin and relationship with other regulatory CD8 T cell subsets remain unclear. In the current study, we examined detailed characteristics and functions of PD-1(+) MP CD8 T cells in naive mice. Their expression pattern of surface molecules resembled that of exhausted CD8 T cells seen in chronic viral infection. However, PD-1(+) MP CD8 T cells were detected from neonatal periods, even in the thymus; thus, they are naturally occurring. By analyzing bone marrow chimera mice in which β(2)-microglobulin-deficient mice were used as the recipients, it was revealed that PD-1(+) MP CD8 T cells were positively selected by hematopoietic cells, indicating that they belong to nonconventional CD8 T cells. However, in contrast to majority of MP CD8 T cells, PD-1(+) MP CD8 T cells were IL-15 independent. PD-1(+) MP CD8 T cells showed the fastest cell cycling among various T cell subsets in naive mice, which was consistent with the highest sensitivity to cyclophosphamide (CP) treatment. Importantly, PD-1(+) MP CD8 T cells were able to suppress delayed-type hypersensitivity response that was augmented by CP treatment. Taken together, our data indicate that the naturally occurring PD-1(+) MP CD8 T cells in naive mice are a unique subset of nonconventional CD8 T cells and represent the CP-sensitive suppressor CD8 T cells.
authors.affiliation: Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sakuraba
authors.forename: Kensuke
authors.initials: K
authors.lastname: Shibata
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshikai
authors.forename: Hisakata
authors.initials: H
authors.lastname: Yamada
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D003520:Cyclophosphamide / Q000494:pharmacology*; D007156:Immunologic Memory / Q000187:drug effects / Q000235:genetics; D016130:Immunophenotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor; D011828:Radiation Chimera / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000943:Antigens, Differentiation; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D003520:Cyclophosphamide