Interleukin-7 is a survival factor for CD4+ CD25+ T-cells and is expressed by diabetes-suppressive dendritic cells.
Dendritic cells can facilitate allograft survival and prevent autoimmunity via direct and indirect cell-mediated mechanisms. Recent studies demonstrate that immunoregulatory dendritic cells (iDCs) confer immune hyporesponsiveness in part through CD4(+) CD25(+) T regulatory cells (Tregs). Herein, we provide evidence to support the hypothesis that dendritic cells derived from NOD mice and engineered ex vivo to exhibit suppressed expression of the CD40, CD80, and CD86 costimulatory molecules motivate an increase in the prevalence of regulatory CD4(+) CD25(+) T-cells via interleukin (IL)-7. Unlike control dendritic cells, these dendritic cells expressed significant levels of IL-7. Exogenous addition of IL-7 to NOD T-cells did not promote expansion or proliferation, but instead selectively maintained the number of CD4(+) CD25(+) T-cells by inhibiting activation of apoptosis in these cells. In vitro, IL-7 receptor alpha-chain (IL-7Ralpha) was expressed at significantly higher levels on CD4(+) CD25(+) T-cells compared with CD4(+) CD25(-) T-cells irrespective of resting or stimulated state. In vivo, CD4(+) CD25(+) T-cells obtained from NOD-scid mice reconstituted with ex vivo engineered iDCs and NOD splenocytes expressed significantly higher levels of IL-7Ralpha compared with levels in the CD4(+) CD25(-) subset, especially in diabetes-suppressive dendritic cell-administered NOD-scid recipients. Taken together, our data suggest a novel mechanism by which iDCs delay autoimmunity through the CD4(+) CD25(+) Treg pathway and suggest IL-7 as a survival factor for these putative Tregs, which express the alpha-chain of its receptor at considerably higher levels than CD4(+) CD25(-) T-cells.
Harnaha
Jo
J
Department of Pathology, University of Pittsburgh School of Medicine, Diabetes Institute, Rangos Research Center, 3460 Fifth Avenue, Pittsburgh, PA 15213, USA.
Machen
Jennifer
J
Wright
Marietta
M
Lakomy
Robert
R
Styche
Alexis
A
Trucco
Massimo
M
Makaroun
Sami
S
Giannoukakis
Nick
N
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003713:Dendritic Cells / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D020395:Receptors, Interleukin-7 / Q000378:metabolism
D015851:Interleukin-7; D015375:Receptors, Interleukin-2; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain