Peptide‐Pulsed Immature Dendritic Cells Reduce Response to β Cell Target Antigens and Protect NOD Recipients from Type I Diabetes

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Abstract
Abstract:  Our previous work demonstrated peptide‐pulsed mature myeloid dendritic cells (DC) presenting β cell antigens induce tolerance. Here we determine whether immature DC (iDC) presenting dominant (insulin β9–23 chain, proinsulin C19–A3) or ignored (glutamic acid decarboxylase 6578‐97) 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 (∼80%), whereas GAD6578–97 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 β 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 β cell antigens, possibly through the induction of regulatory T cells.