Plasmacytoid Dendritic Cells Infiltrate the Skin in Positive Tuberculin Skin Test Indurations

Abstract

Plasmacytoid dendritic cells (pDCs) are rarely present in normal skin but have been shown to infiltrate lesions of infections or autoimmune disorders. Here, we report that several DC subsets including CD123(+) BDCA-2/CD303(+) pDCs accumulate in the dermis in indurations induced by the tuberculin skin test (TST), used to screen immune sensitization by Mycobacterium tuberculosis. Although the purified protein derivate (PPD) used in the TST did not itself induce pDC recruitment or IFN-α production, the positive skin reactions showed high expression of the IFN-α-inducible protein MxA. In contrast, the local immune response to PPD was associated with substantial cell death and high expression of the cationic antimicrobial peptide LL37, which together can provide a means for pDC activation and IFN-α production. In vitro, pDCs showed low uptake of PPD compared with CD11c(+) and BDCA-3/CD141(+) myeloid DC subsets. Furthermore, supernatants from pDCs activated with LL37-DNA complexes reduced the high PPD uptake in myeloid DCs, as well as decreased their capacity to activate T-cell proliferation. Infiltrating pDCs in the TST reaction site may thus have a regulatory effect upon the antigen processing and presentation functions of surrounding potent myeloid DC subsets to limit potentially detrimental and excessive immune stimulation.

Prognostic Significance of CD169+ Lymph Node Sinus Macrophages in Patients with Malignant Melanoma

“…In contrast, we expected that the CD68-negative small-sized IFNa þ cells might be pDCs because it is generally accepted that pDCs produce high amounts of IFNa (27). Double immunostaining demonstrated that these small-sized IFNa þ cells were partially positive for CD303, a marker of pDCs (28). The effect of IFNa may be to influence sinus macrophages through paracrine signaling, because the CD169 þ sinus macrophages were themselves negative for IFNa.…”

Human Plasmacytoid Dendritic Cells Efficiently Capture HIV-1 Envelope Glycoproteins via CD4 for Antigen Presentation

“…Myeloid DCs (MDCs) found in the skin and blood have potent antigen uptake capacity (3) and express a variety of receptors including C-type lectin receptors (CLRs), which they employ for endocytic or phagocytic uptake of exogenous antigen. In contrast, plasmacytoid DCs (PDCs) have a more restricted capacity for uptake of soluble antigen (4–7). Different receptor expression and uptake pathways can lead to different intracellular routing and consequently a different outcome in the mode or efficiency of antigen presentation (5, 8–10).…”

Dendritic cell recruitment in response to skin antigen tests in HIV-1-infected individuals correlates with the level of T-cell infiltration

“…A positive skin-test reaction indicates previous antigenic exposure, T cell competence and an intact inflammatory response. In accordance with the fact that the skin test formulations exclusively induce immune-activation in individuals with pre-existing immunity, we have earlier reported that there is no infiltration of DCs after injection of PPD in non-sensitized individuals who do not display positive TST indurations [22]. The efficiency with which skin test antigen is presented to T cells and with which the DTH reaction develops are likely strongly enhanced by the level of recruitment of DCs to the skin and continuous antigen presentation [23, 24, 33].…”

“…Cell nuclei were counterstained with Mayer’s Haematoxylin (Histolab Products, Gothenburg, Sweden). A blinded analysis of the sections was performed by two separate investigators with a Leica DMR-X microscope (Leica Microsystems GmbH, Wetzlar, Germany) coupled to computerized image analysis (Leica Qwin 5501W, Leica Imaging Systems) as described [22]. Quantification of all markers was performed in the dermis except for Langerin, which was done in the epidermis.…”

“…However, PDCs that do not usually reside in the skin have recently been shown to infiltrate skin lesions caused by herpes and varicella infections, and the level of PDC recruitment to the lesions was shown to correlate with control of infection [18-21]. In addition, we earlier demonstrated that there is a robust infiltration of several distinct DC subsets including PDCs into dermal indurations induced by the tuberculin skin test (TST) [22]. The level of recruitment of functionally different DC subsets to sites of antigen exposure is likely to shape the quality and magnitude of the adaptive response.…”