Depletion and impaired interferon‐α‐producing capacity of blood plasmacytoid dendritic cells in human T‐cell leukaemia virus type I‐infected individuals

Abstract

Summary Dendritic cells (DCs) play an important role in innate and adaptive immunity. There are two major populations of blood DCs, myeloid DCs (myDCs) and plasmacytoid DCs (pcDCs). pcDCs are particularly important in antiviral as well as in general host defence, as they are the principal producers of type I interferons (IFNs). In this study, we analysed myDCs and pcDCs in healthy controls, human T‐cell leukaemia virus type I (HTLV‐I)‐infected asymptomatic carriers (ACs), and patients with adult T‐cell leukaemia (ATL). ATL patients had significantly decreased number of pcDCs and myDCs compared with controls. IFN‐α production by peripheral blood mononuclear cells (PBMCs) was markedly reduced in ATL patients. Purified pcDCs from ACs were found to have impaired IFN‐α‐producing capacity, suggesting a functional defect in pcDCs in HTLV‐I‐infected individuals. Interestingly, pcDCs were shown to be susceptible to HTLV‐I infection. Thus, impaired IFN‐α production by pcDCs may contribute to the immunodeficiency observed in ATL. Furthermore, IFN‐α‐producing capacity was inversely correlated with HTLV‐I proviral load in PBMCs from ACs, suggesting a role for pcDCs in maintaining the carrier state. Taken together, we hypothesize that the depletion and impaired IFN‐α‐producing capacity of blood DCs may contribute to the immunodeficiency in ATL and/or the development of ATL.

Severe loss of invariant NKT cells exhibiting anti–HTLV-1 activity in patients with HTLV-1–associated disorders

“…The decreased frequency of DCs in ATL patients is consistent with a previous report. 44 We are the first to demonstrate the decreased DC frequency in HAM/TSP patients compared with HDs. Whereas the DC frequency in ATL patients was significantly lower, the expression level of CD1d on mDCs, monocytes, and B cells and that of activation markers (CD86 and HLA-ABC) on circulating DCs was similar among the study groups ( Figure 3, supplemental Figure 3).…”

“…45 Moreover, the ability of pDCs from ACs to produce type 1 interferon, an important antiviral mechanism of the innate immune system, is impaired. 44 Further studies must address the effect of HTLV-1 infection on DC functions, especially the function to activate iNKT cells.…”

“…45 Moreover, the ability of pDCs from ACs to produce type 1 interferon, an important antiviral mechanism of the innate immune system, is impaired. 44 Further studies must address the effect of HTLV-1 infection on DC functions, especially the function to activate iNKT cells.Recently, it has been reported that iNKT cells are highly susceptible to HIV-1 infection, and direct infection may be a primary cause of their depletion and functional impairment. 39,40 Therefore, we quantified the rate of infection in iNKT cells in HTLV-1-infected persons to determine whether direct HTLV-1 infection is also an important mechanism underlying the decreased frequency and functional impairment of iNKT cells in such persons.…”

Serological identification of adult T‐cell leukaemia‐associated antigens

“…In the present study, sera obtained from the additional 20 ATL patients were not reactive to SRPK1 protein. It has been reported that T-cell (Kannagi et al, 1991), B-cell (Tanaka et al, 1989) and dendritic cell (Hishizawa et al, 2004b) functions are impaired in HTLV-I-infected individuals. Such immunodeficiency appears to be responsible for the reduced antibody response against SRPK1 in ATL patients despite its high expression, which may limit the usefulness of SRPK1 as a potential target for immunotherapy.…”

slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells

“…We also observed that the uptake of tumour-cell-derived apoptotic bodies by slanDCs is Dectin-1/CLEC7A-and CD18-independent, and that IFNg-activated slanDCs cultured with fluorescent-labelled, alive HT29 cells contained intracellular apoptotic bodies likely derived from the slanDC-mediated killing of HT29 cells, as previously shown 16 . Circulating mDCs and pDCs from cancer patients are frequently reduced in number and functionally defective [30][31][32][33][34] . Recent works have proved the prognostic significance of the immune response to colon carcinomas (CCR) 35,36 .…”