Abstract
Type 1 diabetes (T1D) is a disease caused by the destruction of the beta cells of the pancreas by activated T cells. Dendritic cells (DC) are the APC that initiate the T cell response that triggers T1D. However, DC also participate in T cell tolerance, and genetic engineering of DC to modulate T cell immunity is an area of active research. Galectin-1 (gal-1) is an endogenous lectin with regulatory effects on activated T cells including induction of apoptosis and down-regulation of the Th1 response, characteristics that make gal-1 an ideal transgene to transduce DC to treat T1D. We engineered bone marrow-derived DC to synthesize transgenic gal-1 (gal-1-DC) and tested their potential to prevent T1D through their regulatory effects on activated T cells. NOD-derived gal-1-DC triggered rapid apoptosis of diabetogenic BDC2.5 TCR-transgenic CD4+ T cells by TCR-dependent and -independent mechanisms. Intravenously administered gal-1-DC trafficked to pancreatic lymph nodes and spleen and delayed onset of diabetes and insulitis in the NODrag1(-/-) lymphocyte adoptive transfer model. The therapeutic effect of gal-1-DC was accompanied by increased percentage of apoptotic T cells and reduced number of IFN-gamma-secreting CD4+ T cells in pancreatic lymph nodes. Treatment with gal-1-DC inhibited proliferation and secretion of IFN-gamma of T cells in response to beta cell Ag. Unlike other DC-based approaches to modulate T cell immunity, the use of the regulatory properties of gal-1-DC on activated T cells might help to delete beta cell-reactive T cells at early stages of the disease when the diabetogenic T cells are already activated.
Highlights
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Myeloid Dendritic cells (DC) were generated from bone marrow (BM) cell precursors of NODscid mice and transduced with recombinant adenovirus (RAd)-gal-1-enhanced GFP (eGFP) (MOI ϭ 100)
The presence of tg gal-1 (14 kDa) was confirmed by Western blot analysis in whole cell extracts of NOD BM DC transduced with RAd-gal-1-eGFP (Fig. 1C)
Summary
T1D, type 1 diabetes; gal-1, galectin-1; Treg, regulatory T cell; tg, transgenic; DC, dendritic cell; BM, bone marrow; PLN, pancreatic lymph node; TDG, thiodigalactoside; RAd, recombinant adenovirus; CMVp, CMV promoter; eGFP, enhanced GFP; GAD65206–220, glutamic acid decarboxylase 65 peptide 206 –220; EAE, experimental autoimmune encephalomyelitis; IRES, internal ribosomal entry site; CyC, CyChrome; MOI, multiplicity of infection. The idea that gal-1 may play an important role in peripheral T cell suppression and/or tolerance is supported by previous studies showing that this lectin: 1) triggers apoptosis of activated T cells [4], 2) down-modulates Th1 responses [6], 3) is present in immune-privileged tissues (i.e., brain, placenta, testis) [7,8,9], 4) is used as a mechanism of immunoescape by melanomas [10], and 5) is expressed by regulatory T cells (Treg) [11] In this regard, it has been demonstrated that administration of gal-1 prevents/ameliorates T cell-mediated autoimmune disorders including experimental autoimmune encephalomyelitis (EAE) [12], collagen-induced arthritis [6], and experimental colitis [13] in rodents. The beneficial effect of administration of NOD BM DC expressing tg gal-1 was accompanied by an increased number of apoptotic T cells and decreased number of IFN␥-secreting CD4ϩ T cells in pancreatic lymph nodes (PLN) and substantial reduction of T cell proliferation and IFN-␥ secretion in response to  cell-derived Ag
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