BTLA-Expressing Dendritic Cells in Patients With Tuberculosis Exhibit Reduced Production of IL-12/IFN-α and Increased Production of IL-4 and TGF-β, Favoring Th2 and Foxp3+ Treg Polarization

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.

Roles of BTLA in Immunity and Immune Disorders

“…Jones et al discovered that BTLA + DCs governed the conversion of peripheral Treg cells by upregulating CD5, thus enhancing the tolerance of peripheral Treg cells ( 41 ). Moreover, active pulmonary tuberculosis drives BTLA expression in DCs, thereby inhibiting Th17 and Th22 responses induced by DCs and promoting Treg and Th2 differentiation ( 42 ). Further, urothelial cancer induces the overexpression of BTLA in DCs, resulting in reduced secretion of effector cytokines ( 43 ).…”

BTLA-HVEM Couple in Health and Diseases: Insights for Immunotherapy in Lung Cancer

“…Zhang et al. reported that BTLA + DCs promoted Treg and Th2 polarization of T cells in human lung tuberculosis ( 23 ). Altogether, these data highlight the importance of BTLA in immune homeostasis.…”

Dietary Fatty Acids in Postprandial Triglyceride-Rich Lipoproteins Modulate Human Monocyte-Derived Dendritic Cell Maturation and Activation

“…Upon differentiation, moDCs undergo an activation process that, depending on their membrane receptors and secreted cytokines, means that moDCs may have either a pro-inflammatory or tolerogenic function. Pro-inflammatory activation is with CD80 and CD86 surface marker expression and IL-12p70 cytokine secretion, whereas PD-L1 and PD-L2 surface marker expression and IL-10 cytokine secretion are considered to prompt tolerogenic or anti-inflammatory activation of moDCs [ 6 ]. Any microenvironmental disturbance produces dysfunctional mDCs that may initiate inflammatory or autoimmune diseases.…”