Phenotypically resembling myeloid derived suppressor cells are increased in children with HIV and exposed/infected with Mycobacterium tuberculosis

Abstract

Increased disease susceptibility during early life has been linked to immune immaturity, regulatory T-cell/TH2 immune biasing and hyporesponsiveness. The contribution of myeloid derived suppressor cells (MDSCs) remains uninvestigated. Here, we assessed peripheral MDSC in HIV-infected and -uninfected children with tuberculosis (TB) disease before, during and after TB treatment, along with matched household contacts (HHCs), HIV-exposed, -infected and -uninfected children without recent TB exposure. Serum analytes and enzymes associated with MDSC accumulation/activation/function were measured by colorimetric- and fluorescence arrays. Peripheral frequencies of cells phenotypically resembling MDSCs were significantly increased in HIV-exposed uninfected (HEU) and M.tb-infected children, but peaked in children with TB disease and remained high following treatment. MDSC in HIV-infected (HI) children were similar to unexposed uninfected controls; however, HAART-mediated MDSC restoration to control levels could not be disregarded. Increased MDSC frequencies in HHC coincided with enhanced indoleamine-pyrrole-2,3-dioxygenase (IDO), whereas increased MDSC in TB cases were linked to heightened IDO and arginase-1. Increased MDSC were paralleled by reduced plasma IP-10 and thrombospondin-2 levels in HEU and significantly increased plasma IL-6 in HI HHC. Current investigations into MDSC-targeted treatment strategies, together with functional analyses of MDSCs, could endorse these cells as novel innate immune regulatory mechanism of infant HIV/TB susceptibility.

Macrophage heterogeneity and plasticity in tuberculosis

“…Infected monocytes/macrophages can reach the bone marrow and interact with hematopoietic stem cells (HSCs) and educate them for generating epigenetically modified macrophages that are much more competent in innate immune response than naive macrophages . Myeloid‐derived suppressor cells (MDSCs) can also be recruited at the site of infection and can negatively influence infection control by inhibiting macrophage and T cell responses via the cytokines and chemokines they produce …”

“…MDSCs are another heterogeneous population of early myeloid progenitors of macrophages that are now being reported to participate in M. tuberculosis infection . Arrested at a different stage of differentiation, MDSCs were shown to suppress the adaptive immune response of CD4 and CD8 T cells.…”

“…61,62 Myeloid-derived suppressor cells (MDSCs) can also be recruited at the site of infection and can negatively influence infection control by inhibiting macrophage and T cell responses via the cytokines and chemokines they produce. [63][64][65]68 The role of AMs in the dissemination of M. tuberculosis from alveoli to lung interstitium has recently been demonstrated in a murine TB model. 42 After localization of M. tuberculosis infected AMs to lung interstitium, monocyte-derived macrophages take up the bacilli in a process involving IL-1 receptor mediated signaling between these two subsets of macrophages.…”

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

“…As a potentially novel suppressor mechanism, we identified NO-dependent DC killing in the splenic white pulp T cell areas. Since impaired memory T cell generation and lack of protection have been found also in experimental M. tuberculosis infections of mice (11) and in human TB patients (9,10), our findings in mice may have implications for TB vaccinations in humans and suggest that investigations on potential MDSC induction and DC killing also in human trials should be considered.…”

<p>Paradoxes in the Phenotype, Frequency and Roles of Myeloid-Derived Suppressor Cells During HIV Infection</p>

“…18 In HIV-1/Hepatitis C Virus (HCV) co-infected patients, there was an expansion of mMDSCs which positively correlated with HIV disease markers, including low CD4+ T cell counts and high plasma viral load. 19 Likewise, in children with HIV infection 20 and in patients co-infected with HIV and Cytomegalovirus (CMV), 21 mMDSCs were shown to be the predominant subsets. Recently, a 13-fold increase of the mMDSC (CD14+ MDSC) subset than the gMDSC (Lin-CD15+MDSC) subset was observed in the peripheral blood of SIV infected Indian rhesus macaques.…”