Characterization of a new subpopulation of mouse CD8α+ B220+ dendritic cells endowed with type 1 interferon production capacity and tolerogenic potential

Abstract

We describe a new B220 ؉ subpopulation of immaturelike dendritic cells (B220 ؉ DCs) with low levels of expression of major histocompatibility complex (MHC) and costimulatory molecules and markedly reduced T-cell stimulatory potential, located in the thymus, bone marrow, spleen, and lymph nodes. B220 ؉ DCs display ultrastructural characteristics resembling those of human plasmacytoid cells and accordingly produce interferon-␣ after virus stimulation. B220 ؉ DCs acquired a strong antigen-presenting cell capacity on incubation with CpG oligodeoxynucleotides, concomitant with a remarkable up-regulation of MHC and costimulatory molecules and the production of interleukin-12 (IL-12) and IL-10. Importantly, our data suggest that nonstimulated B220 ؉ DCs represent a subset of physiological tolerogenic DCs endowed with the capacity to induce a nonanergic state of T-cell unresponsiveness, involving the differentiation of T regulatory cells capable of suppressing antigen-specific T-cell proliferation. In conclusion, our data support the hypothesis that B220 ؉ DCs represent a lymphoid organ subset of immature DCs with a dual role in the immune system-exerting a tolerogenic function in steady state but differentiating on microbial stimulation into potent antigen-presenting cells with type 1 interferon production capacity. IntroductionMaintenance of immunologic self-tolerance is an essential process directed at preventing harmful autoimmune diseases caused by autoreactive T cells capable of responding to self-antigens. Avoidance of pathologic reactivity of self-reactive T cells may occur as a consequence of T-cell deletion, T-cell unresponsiveness, or, in some instances, T helper cell type 2 (TH2) skewing (reviewed in Hackstein et al 1 ). Deletion of autoreactive T-cell clones, resulting in T-cell-negative selection, takes place essentially in the thymus under the control of thymic dendritic cells (DCs) and epithelial cells (reviewed in Ardavín 2 ). In contrast, the molecular mechanisms controlling T-cell unresponsiveness or anergy, which is the basis of peripheral tolerance, are not fully understood. However, increasing evidence supports that T regulatory (T reg ) cells play an essential role in the control of autoreactive T-cell clones and, therefore, in the maintenance of T-cell peripheral tolerance because of their capacity to suppress antigen-specific T-cell responses (reviewed in Roncarolo and Levings 3 ). Interestingly immature DCs have been demonstrated to participate in the differentiation of T reg cells (reviewed in Jonuleit et al 4 ). In this sense, human and mouse interleukin-10 (IL-10)-treated immature DCs have been reported to induce antigen-specific T-cell anergy. [5][6][7][8][9] In addition, in vitrogenerated human immature DCs have been demonstrated to induce the differentiation of T reg cells in vitro and in vivo. 9,10 Therefore, on the basis of these data, the tolerogenic potential of DCs has been proposed to be correlated with an immature DC state. 1 On the other hand, DC-mediated induction of murine T-ce...

Absence of cross‐reactivity between murine Ly‐6C and Ly‐6G

“…An additional cell population has recently been identified that stains with both Ly-6C and Ly-6G mAbs (12,13). These cells, termed plasmacytoid dendritic cells, comprise a rare population found in many hematopoietic tissues, including spleen and lymph node.…”

“…Its expression has been studied primarily using the monoclonal antibody (mAb) RB6-8C5 (anti Gr-1), but other monoclonal antibodies (mAbs) have also been developed against this antigen (Ag), including NIMPR-14 (9). Expression of Ly-6G has also recently been described on plasmacytoid dendritic cells (12,13).…”

Liver Dendritic Cells Are Less Immunogenic Than Spleen Dendritic Cells because of Differences in Subtype Composition

“…Immature plasmacytoid DC (pDC) have recently been identified in the spleen, lymph node and bone marrow and have been shown to have the capacity either to induce tolerance in the steady state or to produce IFN-␣ upon CpG or viral stimulation (16). Therefore, we wanted to know whether these cells were also present in the liver.…”

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

“…After this characterization in human, its murine PDC counterpart was then isolated 16– 19 . Human PDC are usually identified as CD4 + , CD303 + (previously known as BDCA-2), and CD123 high , whereas mouse PDC are CD11c int , B220 + , SIGLEC-H + , and CD317 + 7 .…”

“…Receptors expressed by PDC, such as immunoglobulin-like transcript 7 61 or CD303 62 may also inhibit TLR7/9-mediated type I IFN production. In addition, PDC can produce, under certain circumstances, high levels of immunosuppressive cytokines, such as IL-10 19, 25 or TGF-β 56, 63 . In addition, PDC participate in the maintenance of immune tolerance via the induction and/or expansion of regulatory T cells (please refer to Refs# 7, 63 ; this is out of the scope of this review).…”