Abstract
IntroductionDendritic cells (DCs) are capable of inducing immunity or tolerance. Previous studies have suggested plasmacytoid DCs (pDCs) are pathogenic in systemic lupus erythematosus (SLE). However, the functional characteristics of directly isolated peripheral circulating blood pDCs in SLE have not been evaluated previously.MethodsPeripheral blood pDCs from 62 healthy subjects and 58 SLE patients were treated with apoptotic cells derived from polymorphonuclear cells (PMNs). Antigen loaded or unloaded pDCs were then co-cultured with autologous or allogenous T cells. Changes in T cell proliferation, cell surface CD25 expression, intracellular Foxp3 expression and cytokine production were evaluated. pDCs that had captured apoptotic PMNs (pDCs + apoPMNs were also studied for their cytokine production (interferon (IFN)-alpha, interleukin (IL)-6, IL-10, IL-18) and toll like receptor (TLR) expression.ResultsCirculating pDCs from SLE patients had an increased ability to stimulate T cells when compared with control pDCs. Using allogenous T cells as responder cells, SLE pDCs induced T cell proliferation even in the absence of apoptotic PMNs. In addition, healthy pDCs + apoPMNs induced suppressive T regulatory cell features with increased Foxp3 expression in CD4 + CD25 + cells while SLE pDCs + apoPMNs did not. There were differences in the cytokine profile of pDCs that had captured apoptotic PMNs between healthy subjects and patients with SLE. Healthy pDCs + apoPMNs showed decreased production of IL-6 but no significant changes in IL-10 and IL-18. These pDCs + apoPMNs also showed increased mRNA transcription of TLR9. On the other hand, while SLE pDCs + apoPMNs also had decreased IL-6, there was decreased IL-18 mRNA expression and persistent IL-10 protein synthesis. In addition, SLE pDCs lacked TLR9 recruitment.ConclusionsWe have demonstrated that peripheral circulating pDCs in patients with SLE were functionally abnormal. They lacked TLR9 expression, were less capable of inducing regulatory T cell differentiation and had persistent IL-10 mRNA expression following the capture of apoptotic PMNs. We suggest circulating pDCs may be pathogenically relevant in SLE.
Highlights
Dendritic cells (DCs) are capable of inducing immunity or tolerance
T cell proliferation stimulated by plasmacytoid DCs (pDCs) or pDCs + apoPMNs Autologous Mixed leukocyte reaction (MLR) T cell proliferation pDCs from healthy donors (n = 36) did not induce autologous T cell proliferation whether they were fed with apoptotic cells or not (Figure 1a)
No significant differences in the changes in TLR7 and TLR4 mRNA expression in between healthy and systemic lupus erythematosus (SLE) pDCs + apoPMNs were detected (Figure 5a, b)
Summary
Dendritic cells (DCs) are capable of inducing immunity or tolerance. The functional characteristics of directly isolated peripheral circulating blood pDCs in SLE have not been evaluated previously. Dendritic cells (DCs) are professional antigen presenting cells (APCs) with important immunoregulatory functions. They are the only cells that can stimulate naïve T cells [1]. DCs circulate in peripheral tissues, capture pathogens or dying cells, and present antigens to. T cells proliferate and differentiate into Th1 (cell immunity), Th2 (humoral immunity) or T regulatory (Treg) (suppressive) cells resulting in the induction of immunity or tolerance [2]. Recent studies have shown that cytokines produced by DCs contribute to the induction of T cell differentiation [1]. IL-18, previously known as IFN-γ-inducing factor, interacts with IL-
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