Transient upregulation of indoleamine 2,3-dioxygenase in dendritic cells by human chorionic gonadotropin downregulates autoimmune diabetes.
OBJECTIVE
Pregnancy induces a state of immunological tolerance that aims at suppressing immune responses against the fetus and has been linked to temporal remission of preexisting autoimmune disorders. To understand the mechanisms of this reversible immune regulation, we investigated the role of a key pregnancy hormone, human chorionic gonadotropin (hCG), in immune tolerance against autoimmune type 1 diabetes in nonobese diabetic (NOD) mice.


METHODS
We injected hCG into cytokine gene-deficient NOD mice and evaluated the effects of hCG administration on T-cells and dendritic cells (DCs).


RESULTS
We show that administration of hCG to NOD mice inhibits both the activation of diabetogenic CD4(+) and CD8(+) T-cells, in vitro and in vivo, and the progression of type 1 diabetes by upregulating the expression of indoleamine 2,3-dioxygenase (IDO) in DCs. IDO upregulation is transient and declined shortly after hCG withdrawal. DC depletion restores the diabetetogenic activity of splenic T-cells from hCG-treated mice, and inhibition of IDO activity by 1-methyl-tryptophan abrogates the hCG-induced T-cell suppression and resistance to type 1 diabetes.


CONCLUSIONS
We propose that hCG-induced upregulation of IDO in DCs plays a major role in pregnancy-associated resistance to autoimmunity.
Ueno
Aito
A
Julia McFarlane Diabetes Research Centre, Department of Biochemistry and Molecular Biology, University of Calgary, Canada.
Cho
Suzanne
S
Cheng
Lu
L
Wang
Jianxiong
J
Hou
Sheng
S
Nakano
Hiroko
H
Santamaria
Pere
P
Yang
Yang
Y
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D006063:Chorionic Gonadotropin / Q000008:administration & dosage / Q000172:deficiency* / Q000494:pharmacology*; D003713:Dendritic Cells / Q000201:enzymology*; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics*; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000172:deficiency; D015851:Interleukin-7 / Q000172:deficiency; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout
D006063:Chorionic Gonadotropin; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015851:Interleukin-7; D016753:Interleukin-10