Type 1 diabetes patients have significantly lower frequency of plasmacytoid dendritic cells in the peripheral blood
Introduction
The break of tolerance to self-antigens in autoimmune diseases including type 1 diabetes (T1D) is largely due to deficient immune regulation [1], [2]. Although recent studies have focused on the roles of various types of regulatory T cells (Treg), antigen presenting cells, especially dendritic cells (DC), have long been recognized to play a pivotal role in the pathogenesis/protection of autoimmune diseases because they are capable of either priming effector T cells or activating Treg cells depending on the maturation stimuli and/or DC subsets [3], [4], [5]. DC comprises a heterogeneous group of cells and the natural DC population includes two distinct subsets, conventional or myeloid DC (mDC) and plasmacytoid DC (pDC). Analysis of DC subsets in human blood has been difficult due to the lack of specific surface antigens. Recently, a number of novel monoclonal antibodies have been developed and used as blood DC markers [6]. These novel antibodies recognize two subsets of myeloid DC. The mDC1 subset is positive for BDCA1 (CD1c) while the mDC2 subset is positive for BDCA3. pDC were originally identified in human [7] and subsequently identified in mice [8], [9]. Human blood pDC are specifically recognized as cells positive for BDCA2 and BDCA4.
pDC can produce vast amounts of type I interferons in response to viruses and other stimuli and thus play an important role in antiviral immunity and potentially in autoimmunity [10], [11]. Murine immature pDC, when freshly isolated from mouse secondary lymphoid tissue, are endowed with tolerogenic potential by inducing differentiation of Treg [12]. Immature pDC can also induce allogeneic T cell hyporesponsiveness and prolong heart graft survival when they are derived from bone marrow [13]. Human pDC appear to have an intrinsic capacity to prime naïve T cells to dedifferentiate into regulatory T cells [14].
Although DC are believed to be an important player in T1D pathogenesis, the roles of various DC subsets in T1D has only received some attention in recent years. In the NOD mice, pDC cells are increased after treatment with GCSF, which protects against diabetes [15]. The protective role of pDC has recently been demonstrated in NOD mice [16]. Human studies are more limited due to lack of specific markers and the general difficulties associated with patient-based studies, e.g. high individual variability, ethnic/population differences, variation over time and specimen availability. An early study suggested that T1D patients had higher pDC numbers and secreted more IFN-α than normal controls [17], while a more recent study found no difference in the frequencies of total DC or DC subsets between T1D patients and controls but found reduced IFN-α secretion in T1D patients [18]. These inconsistent results are not surprising as both studies had small sample sizes. In contrast, a recent report using larger sample size suggested that pDC numbers and frequencies were reduced in T1D patients [19]. In order to reconcile these controversial reports, we have undertaken a study on human blood DC subsets in a large cohort of T1D patients using the recently discovered DC surface markers. Our study indicates that the frequency of pDC is significantly reduced in T1D patients while mDC1 and mDC2 subsets are not different between T1D and controls.
Section snippets
Human subjects
A total of 147 Caucasian subjects were recruited from the Augusta area in Georgia. Among these subjects, 72 were T1D patients and 75 were normal controls (NC). The demographic information for these subjects is presented in Table 1. Diagnosis of T1D was made using the criteria of the American Diabetes Association by physician scientists with extensive experience in type 1 diabetes. All patients used in this study unambiguously have type 1 diabetes as questionable cases were not included in this
Results
As shown in (Fig. 1), three blood DC subsets (mDC1, mDC2 and pDC) can be clearly identified from whole blood using the Miltenyi Blood DC Enumeration kit. Whole blood samples were analyzed in this study because it requires small blood volume and minimizes sample handling. The frequencies of total blood DC and the three DC subsets in PBMC of normal control and T1D patient groups are shown in (Fig. 2). The frequency of total DC, mDC1 or mDC2 did not differ between T1D patients and controls.
Discussion
DC is believed to play a pivotal role in autoimmune diabetes as they are critical initiators and regulators of T cell-mediated immune responses towards immunity to foreign antigens or tolerance/immunity to self-antigens. An imbalance favoring immunogenic rather than tolerogenic DC function is believed to contribute to diabetes development in T1D. Most of the evidence supporting a role of DC in T1D comes from the studies of the NOD mouse model. Analyses of human monocyte-derived DC indicated
Acknowledgments
This work was partially supported by grants from the National Institutes of Health (2RO1HD37800, 4R33DK069878, 4R33HD050196, 5U24DK58778, 2P01AI-42288) and Juvenile Diabetes Research Foundation International (JDRF 1-2004-661) to JXS.
References (37)
- et al.
Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals
Immunity
(2002) - et al.
Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo
Immunity
(2003) - et al.
Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?
Trends Immunol.
(2002) - et al.
Characterization of a new subpopulation of mouse CD8alpha+ B220+ dendritic cells endowed with type 1 interferon production capacity and tolerogenic potential
Blood
(2002) - et al.
Plasmacytoid dendritic cell precursors induce allogeneic T-cell hyporesponsiveness and prolong heart graft survival
Am. J. Transplant.
(2005) - et al.
Reduced IFN-[alpha] secretion by blood dendritic cells in human diabetes
Clin. Immunol.
(2006) - et al.
Decreased blood dendritic cell counts in type 1 diabetic children
Clin. Immunol.
(2007) - et al.
Impaired primary immune response in type-1 diabetes. Functional impairment at the level of APCs and T-cells1
Cell Immunol.
(2003) - et al.
Defective maturation and function of antigen-presenting cells in type 1 diabetes1
Lancet
(1995) - et al.
Impaired primary immune response in type-1 diabetes: results from a controlled vaccination study2
Clin. Immunol.
(2002)
Characterization of monocyte-derived dendritic cells in recent-onset diabetes mellitus type 11
Clin. Immunol.
Induction of anergic and regulatory T cells by plasmacytoid dendritic cells and other dendritic cell subsets
Hum. Immunol.
CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes
Proc. Natl. Acad. Sci. U. S. A.
Dendritic cell lineage, plasticity and cross-regulation
Nat. Immunol.
Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells
J. Immunol.
BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood
J. Immunol.
Mouse and human dendritic cell subtypes
Nat. Rev. Immunol.
CD11c(+)B220(+)Gr-1(+) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells
J. Exp. Med.
Cited by (0)
- 1
These authors contributed equally to this study.
- 2
Current address: Department of Pediatrics, Emory University, Atlanta, GA, USA.