Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells.
Despite thymic deletion of cells with specificity for self-antigens, autoreactive T cells are readily detectable in the normal T-cell repertoire. In recent years, a population of CD4(+) T cells that constitutively express the interleukin-2 receptor-alpha chain, CD25, has been shown to play a pivotal role in the maintenance of self-tolerance in rodent models. This study investigated whether such a regulatory population exists in humans. A population of CD4(+)CD25(+) T cells, taken from the peripheral blood of healthy individuals and phenotypically distinct from recently activated CD4(+) T cells, was characterized. These cells were hyporesponsive to conventional T-cell stimuli and capable of suppressing the responses of CD4(+)CD25(-) T cells in vitro. Addition of exogenous interleukin-2 abrogated the hyporesponsiveness and suppressive effects of CD4(+)CD25(+) cells. Suppression required cell-to-cell contact but did not appear to be via the inhibition of antigen-presenting cells. In addition, there were marked changes in the expression of Notch pathway molecules and their downstream signaling products at the transcriptional level, specifically in CD4(+)CD25(+) cells, suggesting that this family of molecules plays a role in the regulatory function of CD4(+)CD25(+) cells. Cells with similar phenotype and function were detected in umbilical venous blood from healthy newborn infants. These results suggest that CD4(+)CD25(+) cells represent a population of regulatory T cells that arise during fetal life. Comparison with rodent CD4(+)CD25(+) cells suggests that this population may play a key role in the prevention of autoimmune diseases in humans.
Ng
W F
WF
Department of Immunology, Hammersmith Campus, Imperial College School of Medicine, London, United Kingdom.
Duggan
P J
PJ
Ponchel
F
F
Matarese
G
G
Lombardi
G
G
Edwards
A D
AD
Isaacs
J D
JD
Lechler
R I
RI
D000328:Adult; D000938:Antigen-Presenting Cells; D001327:Autoimmune Diseases / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D002450:Cell Communication; D018929:Cell Culture Techniques; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D006801:Humans; D007231:Infant, Newborn; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D014157:Transcription Factors; D014158:Transcription, Genetic
D007376:Interleukin-2; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D010835:Phytohemagglutinins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2; D014157:Transcription Factors