Cytotoxic Activity of Dendritic Cells as a Possible Mechanism of Negative Regulation of T Lymphocytes in Pulmonary Tuberculosis

Abstract

The PD-1/B7-H1-mediated induction of T cell apoptosis/anergy as a possible mechanism of immune response failure was studied in 76 patients with pulmonary tuberculosis (TB) with normal and low-proliferative response to antigens of M. tuberculosis (purified protein derivative (PPD)). It was revealed that dendritic cells (DCs), generated in vitro from patient blood monocytes with GM-CSF + IFN-α, were characterized by increased B7-H1 expression, upproduction of IL-10, and reducing of allostimulatory activity in mixed lymphocyte culture (MLC). Moreover, DCs of patients with TB were able to enhance T cell apoptosis and to block T-cell division in MLC. It was shown that neutralizing anti-PD1 antibodies significantly decreased the proapoptogenic/tolerogenic effect of DCs. Correlation analysis revealed a direct relationship between IL-10 production and level of B7-H1 expression in the general group of investigated patients. It was demonstrated that generation of healthy donor DCs in the presence of IL-10 led to an increase in the number of DCs-expressed B7-H1 molecule, DC proapoptogenic activity, and a decrease in their allostimulatory activity. Obviously, the revealed phenomenon of the PD-1/B7-H1-mediated pro-apoptogenic activity of DCs is clinically significant since the cytotoxic/tolerogenic potential of DCs is more pronounced in patients with PPD anergy.

Low Antigen-specific T-cell Response in Pulmonary Tuberculosis is Associated with Impaired Phenotype and Functions of Interferon-α Induced Dendritic Cells

“…The data obtained are consistent with those of Rajashree et al, which studied monocyte-derived DCs generated in presence of GM-CSF and IL-4 and found the inhibition of DC differentiation/maturation in pulmonary TB patients [18]. Besides, we for the first time have demonstrated that patient DCs had the increased expression of B7-H1 (PD-L1), known to induce T cell apoptosis and anergy upon interactions with PD-1 on T-cells [23]. The impairment of IFN-DC differentiation/activation in TB patients was associated with marked DCs dysfunction, in particular with altered cytokine production, decreased allostimulatory activity and the shift toward T2-stimulatory activity.…”

“…From this point of view, the prevalent T2-stimulating activity of IFN-DCs we have found in patients with active TB and especially in PPD-anergic patients, suggests that the DC alterations may be the cause of Th1 deficiency in pulmonary tuberculosis. Generally, the decreased allostimulatory activity, the dominance of T2 stimulating activity and the increased production of IL-10 along with our previous data on pro-apoptogenic activity of patient DCs [23], give evidence of "tolerogenic" phenotype of monocyte-derived DCs in TB infection. The engagement of PD-1/ PD-L1 (B7-H1) signaling pathway in DC cytotoxic activity was also demonstrated during tumor growth and in virus infections [28,30].…”

Regulatory Multitasking of Tolerogenic Dendritic Cells – Lessons Taken from Vitamin D3-Treated Tolerogenic Dendritic Cells

“…The ability of DCs to kill target cells that could serve in anti-tumor immunity or T-cell killing in autoimmunity and transplantation has been described (Chauvin and Josien, 2008). A recent study in pulmonary tuberculosis patients confirms the cytotoxic activity of DCs as a mechanism of negative regulation of T lymphocytes (Sakhno et al, 2012). In case of VD3-DCs, this action is antigen-dependent but not restricted to naïve T cells since VD3-DCs also block IFNγ and IL-10 production and induce active killing of a diabetogenic Th1 clone in an antigen-specific manner (van Halteren et al, 2002).…”

Tumoricidal activity of human dendritic cells

“…Despite their seemingly preferential tumor-directed action, under certain circumstances, MoDCs can induce T cell death [21,32,37]. This observation was made in several studies ( Table 1); all of which were performed in the context of infectious diseases [21,32,37]. The first study demonstrated that MoDCs infected with measles virus can induce paracrine killing of autologous T cells [19].…”

“…Conversely, another study found that CD40 ligation inhibits TRAIL expression in MoDCs, but the cytotoxic ability of these CD40L-matured MoDCs was preserved, suggesting TRAIL-independent mechanisms for induction of cell death [28]. Indeed, as outlined in Table 1, both cell contact-dependent and -independent mechanisms have been implicated in MoDC-mediated killing and their cytolytic armamentarium includes, in addition to TRAIL, a broad range of cytotoxic effector molecules such as TNFa [21][22][23][24]29,30], FAS-L [20][21][22]29,31,32], caspase-8 [19,[33][34][35], lymphotoxin (LT)-a1b2 [29], TNF-like weak inducer of apoptosis (TWEAK) [21], IFN-g [28], granzyme B [27,36], and programmed death ligand (PD-L1/2) [32,37].…”