Abstract
Abstract Type 1 diabetes (T1D) results from adaptive autoimmune destruction of insulin-producing beta cells in pancreatic islets. Macrophages and dendritic cells (DCs) have also been implicated in the disease process, although their roles are less well-studied than those of T cells. S100A4 is a small calcium-activated molecule that contributes to cancer metastases and fibrosis, and has recently been linked to autoimmunity. We have discovered S100A4 among inflammatory infiltrates in pancreatic islets in a T1D model. Cells expressing S100A4 bear surface markers associated with antigen-presentation, such as MHCII and CD86. These cells include CD11c+ DCs, CD11b+ macrophages, and CD11b+/CD11c+ myeloid populations. Neither plasmacytoid DCs (PDCA1+/Ly6C+/B220+) nor lymphoid DCs (CD8+) express S100A4. S100A4-deficiency was engineered by GFP-targeting and introgressed onto the nonobese diabetic (NOD) mouse model of T1D for >10 generations. S100A4-/-/NOD mice are protected from the development of T1D, with a concomitant reduction in insulitis. However, GFP-expression in S100A4-deficient cells indicates that these cell populations remain in the inflamed islets. When compared to S100A4-sufficient counterparts, S100A4-deficient bone marrow-derived DCs have decreased ability to upregulate CD86, or to present antigen and activate T cells in vitro. Thus, S100A4 may contribute to the development of T1D by supporting myeloid cell antigen-presentation to autoreactive T cells.
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