Kinetics of immune cell responses in the multiple low dose streptozotocin mouse model of type 1 diabetes

Abstract

Abstract In type 1 diabetes (T1D), the insulin producing β cells are damaged by immune attacks. It has been hypothesized that the very first response in T1D onset comes from innate immune cells, which further activates the adaptive immune cells to attack the β cells. The kinetics of the infiltration of different immune cells in the multiple low dose streptozotocin (MLDSTZ) induced T1D mouse model is still unclear. Therefore, we used flow cytometry to investigate the proportions of innate immune cells such as neutrophils, dendritic cells (DCs), plasmacytoid DCs (pDCs) and macrophages, and adaptive immune cells (T and B lymphocytes) in thymi, pancreatic draining lymph nodes (PDLNs) and spleens of MLDSTZ mice on days 3, 7, 10 and 21 after the first injection of MLDSTZ. The proportions of DCs and pDCs were increased on day 3 while the proportions of B-1a lymphocytes and neutrophils were increased on day 10 in MLDSTZ treated mice, illustrating that the initial immune response is induced by DCs and pDCs. The proportions of T helper 1, Helios+ T cells and cytotoxic T cells were increased from day 7, suggesting that the innate immune cells precede the adaptive immune cell response in MLDSTZ mice. We also found the proportions of interleukin-35 (IL-35) expressing tolerogenic antigen presenting cells (tolAPCs) were decreased in the spleens of MLDSTZ mice than in control mice on day 21. Furthermore, we found the proportions of IL-35+ tolAPCs were decreased in the peripheral blood mononuclear cells from T1D patients than from healthy controls. Altogether, our data demonstrate a possible sequence of events regarding the involvement of DCs, pDCs, B-1a lymphocytes, neutrophils, and Helios+ T-cells at the early stage of T1D development.