Heat-killed Mycobacterium tuberculosis prime-boost vaccination induces myeloid-derived suppressor cells with spleen dendritic cell–killing capability

Abstract

models of live Mycobacterium tuberculosis infection (11). Whether vaccines containing killed M. tuberculosis would also induce MDSCs remains unclear.Among the carrier substances for antitumor or antipathogen vaccines, incomplete Freund's adjuvant (IFA), used under the name Montanide ISA-51 VG, is a suitable and widely distributed mineral oil-based adjuvant for human clinical studies with good antigen responses but also some adverse effects (12,13). Another preparation, CFA, was developed in 1942 and since then has been widely used as a vaccine adjuvant in experimental animals (14). Since CFA is composed of IFA containing heat-killed and dried M. tuberculosis, it can be considered as an M. tuberculosis vaccine. Notably, unclear tolerogenic effects had been observed after CFA vaccination in animals (14). On the one hand, CFA is a critical component for the induction of autoimmunity in models of experimental autoimmune encephalomyelitis (15, 16); on the other hand, injection of CFA could also prevent autoimmunity, such as the onset of type I diabetes in NOD mice (17) and ameliorated Parkinson's disease in rats (18). While the pathogen-induced adjuvant effects can be explained by mycobacterial triggering of TLR2 and TLR4, the tolerogenic mechanisms of CFA are not understood. The possible suppressive effects, besides their immunostimulatory function by IFA and other adjuvants in tumor vaccination studies, have been reviewed before (13). CFA-based tumor vaccines could induce suppressive CD11b + immune cells (7,19), while in an alum-based vaccine, B cell immune responses were boostered by CD11b + cells (19). However, these questions remain unclear: whether M. tuberculosis or IFA/Montanide will be able to induce MDSCs, which MDSC subsets will become activated, and what are the major target cells of their suppression in vivo.Previously, we described a simple and reliable protocol to generate murine MDSCs in vitro from murine BM precursor cells with . The generation of such human or murine M-MDSCs in vitro can be performed by following a 2-step protocol that, first, converts classical monocytes (Ly6C hi or CD14 + ) into monocytes "licensed" for suppression (L-Mono) that also can be considered as resting M-MDSCs and, second, converts L-Mono into activated M-MDSCs that release the suppressor molecules NO in the murine and IDO in the human system (21). This in vitro differentiation model exemplifies the 2 steps of signaling for M-MDSC induction that are relevant also in vivo (1). While the combination of LPS and IFN-γ for the second step of MDSC activation constituted one of the strongest signals (22), cocktails of proinflammatory cytokines were also effective (21). While the infiltration of MDSCs at vaccination sites and lymph nodes has been observed before using Mycobacterium bovis BCG, only local T cell responses seemed to be affected in these organs (23).The targets of MDSC-mediated suppression were mainly identified as macrophages, NK cells, and CD4 + or CD8 + T cells that were tested for their phagocytic activity, proli...

Analysis of the Myeloid-Derived Suppressor Cells and Annexin A1 in Multibacillary Leprosy and Reactional Episodes

“…The presence of M-MDSCs in high number was observed in the patients with LL and T2R patients with BCG vaccination scar. Some studies have described that the BCG vaccination or inoculation with M. tuberculosis antigens induce the MDSC migration [35,36]. This data and other genetic polymorphisms might make those patients more susceptible to developing the worst symptoms of leprosy.…”

VLA-1 Binding to Collagen IV Controls Effector T Cell Suppression by Myeloid-Derived Suppressor Cells in the Splenic Red Pulp

“…However, no differences were found for the cell subset frequencies ( Figure 1D ). LPS/IFN-γ represents a strong inducer of MDSC activation (A-MDSCs) leading to the release of NO as a major suppression mechanism for T cells ( 5 ) and dendritic cells ( 9 ). A-MDSCs showed no difference in their VLA-1 expression as compared to R-MDSCs.…”

“…In mycobacteria-vaccinated mice MDSC accumulation occurred preferentially in the red pulp and bridging channels. An inflammatory challenge directed them into the white pulp and activated them to induce dendritic cells (DC) killing but left the white pulp T cells unaffected ( 9 ).…”

Caveolin-1 Controls Vesicular TLR2 Expression, p38 Signaling and T Cell Suppression in BCG Infected Murine Monocytic Myeloid-Derived Suppressor Cells

“…Deficiency in arginine-1 inhibits T cell proliferation by impairing CD3 ζ-chain synthesis, which as a consequence prevents upregulation of the expression of cell cycle regulators cyclin D3 and cyclin-dependent kinase 4 (54). NO suppresses T cell function by inducing T cell apoptosis or blocking JAK3 and STAT5 function in T cells (53) or by killing DCs (5). We observed that Cav1 −/− MDSCs displayed defects in the NO production and T cell suppression.…”

“…We found that MDSCs were expanded in the blood of TB patients and decreased after successful chemotherapy (4), and that vaccinations using Mtb can accumulate MDSCs in the spleens of mice (5). In a murine model of TB infection, MDSCs phagocytosed Mtb and secreted IL-10, IL-6, and IL-1α (6).…”