Abstract
Tuberculosis patients and mice infected with live Mycobacterium tuberculosis (Mtb) accumulate high numbers of myeloid-derived suppressor cells (MDSCs). Here, we hypothesized that also dead Mtb vaccines may induce MDSCs that could impair the efficacy of vaccination. We found that repeated injections of Mtb vaccines (heat-killed Mtb in Incomplete Freund's Adjuvant, like Montanide) but not single or control vaccines without Mtb strongly expanded CD11b+ myeloid cells in the spleen, that suppressed T cell proliferation and killing ex vivo. Dead Mtb vaccination induced the generation of CD11b+ Ly-6Chigh CD115+ iNOS/Nos2+ monocytic MDSCs (M-MDSCs) upon application of inflammatory or microbial activation signals. In vivo these M-MDSCs positioned strategically in the spleen by infiltrating the splenic bridging channels and white pulp areas. Notably, within 6 to 24 hours in a Nos2-dependent fashion they produced NO to rapidly kill conventional and plasmacytoid dendritic cells (cDCs, pDCs) while, surprisingly, sparing T cells in vivo. Thus, we demonstrate that Mtb vaccine induced M-MDSCs to not directly suppress T cell in vivo but, instead, M-MDSCs directly target DC subpopulations thereby indirectly suppressing effector T cell responses. Collectively, we demonstrate that Mtb booster vaccines induce M-MDSCs in the spleen that can be activated to kill DCs cautioning to thoroughly investigate MDSC formation in individuals after Mtb vaccination in clinical trials.
Highlights
Myeloid-derived suppressor cells (MDSCs) negatively regulate cell-mediated immunity by inhibiting T cell proliferation and inducing Treg responses [1]
To examine how M. tuberculosis vaccines influence the composition of the myeloid compartment and MDSC generation and activation, most of the following experiments were performed according to defined protocols of immunization
To gain a more detailed insight on the phenotype of CFA-expanded cells, we employed markers frequently used for the identification of MDSCs for immunofluorescence staining of spleens from CFA-treated mice
Summary
Myeloid-derived suppressor cells (MDSCs) negatively regulate cell-mediated immunity by inhibiting T cell proliferation and inducing Treg responses [1]. Among many different suppressor mechanisms of MDSCs [2], the production of NO by the activity of the inducible NO synthase (iNOS) appears to be a suppressive tool mainly described for the monocytic MDSC (M-MDSC) subset [3]. To date, NO production and its direct role in T cell suppression have been shown only in cocultures of T cells stimulated for proliferation with MDSCs in vitro and ex vivo [4,5,6,7]. The demonstration of direct NO-dependent T cell suppression by MDSCs in vivo is lacking.
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