title: Regulation of murine chronic colitis by CD4+CD25- programmed death-1+ T cells.
abstract: Naturally arising CD4(+)CD25(+) regulatory T (T(R)) cells are engaged in the maintenance of self tolerance and prevention of autoimmune diseases. However, accumulating evidence suggests that a fraction of peripheral CD4(+)CD25(-) T cells also possesses regulatory activity. Programmed death-1 (PD-1) is a new member of the CD28/CTLA-4 family, which has been implicated in the maintenance of peripheral self tolerance. Here, we identified a subpopulation of CD4(+)CD25(-)PD-1(+) T cells in the spleen of naive mice that constitutively expressed CTLA-4 and FoxP3 and was hypoproliferative in response to anti-CD3 antibody stimulation in vitro. However, the CD4(+)CD25(-)PD-1(+) T cells uniquely produced large amounts of IL-4 and IL-10 in response to anti-CD3 and anti-CD28 mAb stimulation, unlike the CD4(+)CD25(+) T(R) cells. The CD4(+)CD25(-)PD-1(+) T cells exhibited a suppressor activity against the proliferation of anti-CD3 antibody-stimulated CD4(+)CD25(-)PD-1(-) T cells in vitro, which was partially abrogated by anti-CTLA-4 mAb, but not by anti-IL-10 or anti-PD-1 mAb. Remarkably, the CD4(+)CD25(-)PD-1(+) T cells inhibited the development of colitis induced by adoptive transfer of CD4(+)CD45RB(high) T cells into C.B17-scid/scid mice, albeit to a lesser extent than CD4(+)CD25(+) T(R) cells, in a CTLA-4-dependent manner. These results indicate that the CD4(+)CD25(-)PD-1(+) T cells contain substantial amounts of T(R) cells that are involved in the maintenance of peripheral tolerance.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Teruji
authors.initials: T
authors.lastname: Totsuka
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Shin
authors.initials: S
authors.lastname: Makita
authors.forename: Rei
authors.initials: R
authors.lastname: Fujii
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nemoto
authors.forename: Shigeru
authors.initials: S
authors.lastname: Oshima
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okamoto
authors.forename: Akemi
authors.initials: A
authors.lastname: Koyanagi
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D000954:Antigens, Surface / Q000032:analysis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D060908:CTLA-4 Antigen; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D061026:Programmed Cell Death 1 Receptor; D015375:Receptors, Interleukin-2 / Q000032:analysis*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D015375:Receptors, Interleukin-2; D015847:Interleukin-4