Peptide-pulsed immature dendritic cells reduce response to beta cell target antigens and protect NOD recipients from type I diabetes.
Our previous work demonstrated peptide-pulsed mature myeloid dendritic cells (DC) presenting beta cell antigens induce tolerance. Here we determine whether immature DC (iDC) presenting dominant (insulin beta9-23 chain, proinsulin C19-A3) or ignored (glutamic acid decarboxylase 65(78-97)) antigen determinants promote tolerance. Nonobese diabetic (NOD) mice were given injections of either unpulsed or peptide-pulsed myeloid iDC beginning at 9 weeks of age for 3 consecutive weeks. Diabetes incidence in recipients of unpulsed iDC was comparable to unmanipulated animals ( approximately 80%), whereas GAD65(78-97) pulsed iDC recipients were protected from the disease (P = 0.05). We also analyzed splenic T cell proliferation responses to the panel of studied peptides in diabetic and nondiabetic recipients. When stimulated with insulin or proinsulin peptide, nondiabetic mice receiving the peptide-pulsed iDC had a 21- to 31-fold or 3.9- to 9.0-fold reduction in T cell response, respectively, as compared to the response of diabetic unpulsed recipients. However, only a 2.6- to 3.1-fold reduction in response to beta chain peptide, and a 1.5- to 3.4-fold reduction in proinsulin response were observed in diabetic mice receiving peptide-pulsed iDC. The reduction was not specific to the immunizing peptide, as reduced proliferation was observed to other diabetes-target peptides. We conclude that protective iDC-based therapies require target antigen presentation, and ignored determinants may be preferable perhaps due to an available naïve T cell repertoire. In addition, iDC presenting peptides induce a nonspecific reduction in T cell responses to beta cell antigens, possibly through the induction of regulatory T cells.
Lo
Jeannette
J
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA.
Peng
Rui Hua
RH
Barker
Tolga
T
Xia
Chang-Qing
CQ
Clare-Salzler
Michael J
MJ
D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D007108:Immune Tolerance; D007328:Insulin / Q000494:pharmacology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology
D000941:Antigens; D007328:Insulin; D010446:Peptide Fragments; D005968:Glutamate Decarboxylase