Abstract
Little is known about how tuberculosis (TB) impairs dendritic cell (DC) function and anti-TB immune responses. We previously showed that the B and T lymphocyte attenuator (BTLA), an immune inhibitory receptor, is involved in TB pathogenesis. Here, we examined whether BTLA expression in TB affects phenotypic and functional aspects of DCs. Active TB patients exhibited higher expression of BTLA in myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) subsets compared with healthy controls (HCs). BTLA expression was similarly high in untreated TB, TB relapse, and sputum-bacillus positive TB, but anti-TB therapy reduced TB-driven increases in frequencies of BTLA+ DCs. BTLA+ DCs in active TB showed decreased expression of the DC maturation marker CD83, with an increased expression of CCR7 in mDCs. BTLA+ DCs in active TB displayed a decreased ability to express HLA-DR and to uptake foreign antigen, with a reduced expression of the co-stimulatory molecule CD80, but not CD86. Functionally, BTLA+ DCs in active TB showed a decreased production of IL-12 and IFN-α as well as a reduced ability to stimulate allogeneic T-cell proliferative responses. BTLA+ mDCs produced larger amounts of IL-4 and TGF-β than BTLA− mDCs in both HCs and APT patients. BTLA+ DCs from active TB patients showed a reduced ability to stimulate Mtb antigen-driven Th17 and Th22 polarizations as compared to those from HCs. Conversely, these BTLA+ DCs more readily promoted the differentiation of T regulatory cells (Treg) and Th2 than those from HCs. These findings suggest that TB-driven BTLA expression in DCs impairs the expression of functional DC surrogate markers and suppress the ability of DCs to induce anti-TB Th17 and Th22 response while promoting Th2 and Foxp3+ Tregs.
Highlights
Tuberculosis (TB) remains a leading cause of mortality among infectious diseases, with 10.4 million new cases and 1.7 million deaths in 2016 [1]
B and T lymphocyte attenuator (BTLA) expression in Dendritic cells (DC) in patients with active pulmonary tuberculosis (APT) has not been reported, we previously found that BTLA was highly expressed in CD11c+ antigen-presenting cells (APC) in active TB patients [26]
Representative flow cytometry data are shown in Figure 1. total DCs (tDCs) from TB patients and healthy controls (HCs) showed a lack of differences in BTLA-expression and BTLA mean fluorescence intensity (MFI) (Figure 1A)
Summary
Tuberculosis (TB) remains a leading cause of mortality among infectious diseases, with 10.4 million new cases (including 600,000 new cases with resistance to rifampicin, the most potent first-line drug) and 1.7 million deaths in 2016 [1]. The chronic nature of this infection implies that Mtb has developed strategies to avoid clearance by the innate and adaptive immune responses [4, 5]. Dendritic cells (DC) are the major antigen-presenting cells (APC) in the immune system and play a critical role in adaptive immunity by activating naïve T cells, maintaining tolerance to self-antigens, and bridging the innate and adaptive responses [6]. The mDCs express CD11c, require granulocyte-macrophage colony-stimulating factor (GM-CSF) for growth, survival, and antigen uptake, and play roles in T cell activation and secretion of interleukin (IL)-12 and IL-18. Immature DCs undergo a transformation process that includes up-regulation of class I and class II MHC molecules and co-stimulatory molecules (such as CD80 and CD86), production of IFNs and pro-inflammatory cytokines (IL-12, IL-15, IL-18, and IL-10), and radical changes in the chemokine receptor and adhesion molecule profiles [9, 11,12,13]. The activated mature DCs migrate to the lymphoid organs, where they interact with and stimulate both naïve and primed T cells [11, 12]
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