IL-35 producing antigen presenting cells in type 1 diabetes

Abstract

Abstract In type 1 diabetes (T1D), the insulin producing β cells are damaged by unknown factors. Antigen presenting cells (APCs) are believed to present autoantigens to T cells, thus initiating the immune attacks to β cells. However, several types of APCs also possess regulatory functions by producing anti-inflammatory cytokines like IL-35. We found the proportions of IL-35+ cells among both CD11c+CD123− dendritic cells (DCs) and CD11c−CD123+ DCs were decreased in the peripheral blood mononuclear cells from T1D patients than healthy controls. Multiple low dose streptozotocin (MLDSTZ) mouse model of T1D was used to study the immune response of IL-35 producing APCs. Male CD-1 mice were injected with STZ for five consecutive days to induce experimental T1D. We found the proportions of IL-35 expressing MHC-II+CD11b−CD11chigh conventional DCs (cDCs) were decreased in the spleens of MLDSTZ mice than in control mice on day 21 after the first STZ injection. We next investigated which subtype of cDCs contribute to the IL-35 production, and found that it is CD8+XCR1+ cDC1s that produce IL-35 while cDC2s do not. After the five day STZ injections, male CD-1 mice further received recombinant mouse IL-35 injection or PBS daily for 8 days. We found increased proportions of IL-35+ cells among cDC1s in IL-35 treated mice than PBS treated mice. Only a minority of plasmacytoid DCs (pDCs) produce IL-35, and IL-35 treatment did not increase the proportion of IL-35+ pDCs. We further investigated macrophage polarization, finding that IL-35 treatment increased Arg1+ M2 proportions and decreased TNF-α+ M1 proportions. Our results illustrate that the decrease in IL-35 producing APCs may contribute to the development of T1D.