Swift Intrahepatic Accumulation of Granulocytic Myeloid-Derived Suppressor Cells in a Humanized Mouse Model of Toxic Shock Syndrome

Abstract

Toxic shock syndrome (TSS) and other superantigen-mediated illnesses are associated with 'systemic' immunosuppression that jeopardizes the host's ability to fight pathogens. Here, we define a novel mechanism of 'local' immunosuppression that may benefit the host. Systemic exposure to staphylococcal enterotoxin B (SEB) rapidly and selectively recruited CD11b(+)Gr-1(high)Ly-6C(+) granulocytic myeloid-derived suppressor cells (MDSCs) to the liver of HLA-DR4 transgenic mice. Hepatic MDSCs inhibited SEB-triggered T cell proliferation in a reactive oxygen species-dependent manner, and ex vivo-generated human MDSCs also similarly attenuated the proliferative response of autologous T cells to SEB. We propose a role for MDSCs in mitigating excessive tissue injury during TSS.

Heterogeneity of Ly6G+Ly6C+Myeloid-Derived Suppressor Cell Infiltrates during Staphylococcus aureus Biofilm Infection

“…However, upon arrival, factors within the microenvironment, host and/or pathogen derived, arrest MDSCs in an immature state, and local proinflammatory signals lead to their acquisition of immunosuppressive properties (16). Our laboratory was the first to demonstrate a role for MDSCs in S. aureus biofilms, which has subsequently been confirmed by other groups using distinct S. aureus infection models (12,(20)(21)(22)(23). In our studies, Ly6G ϩ Ly6C ϩ MDSCs were found to infiltrate S. aureus biofilms and establish an anti-inflammatory milieu leading to persistent infection (10,12).…”

“…Indeed, our laboratory has reported minor contributions of PMNs to the immune response during S. aureus biofilm infection, suggesting that biofilms also circumvent significant PMN recruitment by a currently unknown mechanism(s) (11,12,35). Rather, MDSCs are beginning to be recognized as an important player in the pathogenesis of several types of S. aureus infection, including biofilms (10)(11)(12)(20)(21)(22)(23). Whereas PMNs are classically identified as highly differentiated cells specialized for defense against bacterial infection, MDSCs are a heterogeneous population of immature myeloid cells with suppressive immunoregulatory properties that allow S. aureus biofilm persistence (10)(11)(12).…”

Staphylococcal Enterotoxins Dose-Dependently Modulate the Generation of Myeloid-Derived Suppressor Cells

“…So far, all reported pathogens and associated virulence factors either led to an induction or inhibition of MDSC (Ost et al, 2016 ). Examples for induction include, but are not limited to, S. aureus, Pseudomonas aeruginosa /flagellin, Klebsiella pneumonia , or pathogenic fungi (Poe et al, 2013 ; Rieber et al, 2013 , 2015 ; Heim et al, 2014 ; Skabytska et al, 2014 ; Tebartz et al, 2015 ; Szabo et al, 2016 ). An inhibitory effect as seen with staphylococcal enterotoxins at increased concentrations has been observed for the TLR3 agonist Poly (I:C) (Ho et al, 2015 ).…”

“…The authors concluded that this rapid influx was not due to proliferation or generation of MDSC but rather due to homing signals to the liver from the bone marrow. The exact pathways, however, are a matter of future investigation (Szabo et al, 2016 ). A cytotoxic effect of enterotoxins on MDSC was not described in that study.…”

“…(ii) Tebartz et al described a predominant immunosuppressive effect of MDSC compared to regulatory T cells for the chronicity of S. aureus infections (Tebartz et al, 2015 ). (iii) On the other hand ameliorated disease courses have also been described under the influence of MDSC, e.g., in mouse models of acute staphylococcal toxic shock syndrome caused by staphylococcal enterotoxin B (Szabo et al, 2016 ) and of atopic dermatitis with S. aureus colonized skin (Skabytska et al, 2014 ).…”