Regulation of murine chronic colitis by CD4+CD25- programmed death-1+ T cells.
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.
Totsuka
Teruji
T
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Kanai
Takanori
T
Makita
Shin
S
Fujii
Rei
R
Nemoto
Yasuhiro
Y
Oshima
Shigeru
S
Okamoto
Ryuichi
R
Koyanagi
Akemi
A
Akiba
Hisaya
H
Okumura
Ko
K
Yagita
Hideo
H
Watanabe
Mamoru
M
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*
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