Lung myeloid-derived suppressor cells and regulation of inflammation.

Myeloid-derived suppressor cells (MDSCs) have been investigated largely in the context of tumor progression. In contrast to the negative connotation of MDSCs in cancer immunity, our laboratory has recently reported on the development and role of pulmonary MDSC-like cells (CD11b(+)Gr1(int)F4/80(+)) in the regulation of allergic airway inflammation. These regulatory cells were expanded in a TLR4/MyD88-dependent manner and were both phenotypically and morphologically similar to those described in the tumor microenvironment. Although bacterial lipopolysaccharide (LPS) was initially described as an adjuvant in the development of allergic inflammation, subsequent studies showed that this is true only at relatively low doses of LPS. A high dose of LPS was shown to actually suppress eosinophilic airway inflammation. In our efforts to understand the mechanism underlying LPS-mediated suppression of allergic airway disease, we recently showed that LPS induces MDSC-like cells in the lung tissue in a dose-dependent manner, with increased accumulation of the cells at high doses of LPS. In contrast to lung dendritic cells (DCs), the MDSC-like cells did not traffic to the lung-draining lymph nodes, allowing them to act in a dominant fashion over DCs in the regulation of Th2 responses. The MDSC-like cells were found to blunt the ability of the lung DCs to upregulate GATA-3 or to promote STAT5 activation in primed Th2 cells, both transcription factors having critical roles in Th2 effector function. Thus, a complete understanding of the generation and regulation of the lung MDSCs would provide novel options for therapeutic interventions.

LPS-induced CD11b+Gr1(int)F4/80+ regulatory myeloid cells suppress allergen-induced airway inflammation.

In humans, the bacterial product lipopolysaccharide (LPS) has been associated with protection from allergic diseases such us asthma. However, in mouse models of allergic asthma, differential effects of LPS have been noted based on the dose. A low dose of LPS promotes Th2 responses and allergic disease but a high dose has been associated with suppression of allergic airway inflammation. Our recent work has described the ability of LPS to increase the frequency of CD11b+Gr1(int)F4/80+(abbreviated as Gr1(int) cells) cells in the lung tissue of mice in a dose-dependent fashion that is dependent on TLR4 and the TLR adaptor protein, MyD88. Both phenotypically and morphologically, the cells were found to have similarities with mycloid-derived suppressor cells. Adoptive transfer of LPS-induced Gr1(int) cells suppressed allergen-induced airway inflammation suggesting regulatory functions of the cells in allergic asthma. Although the Gr1(int) cells are detectable in the lung tissue of LPS-treated mice, they are barely detectable in the lung-draining lymph nodes (Lns) or in the airway lumen. This causes selective enrichment of these cells over dendritic cells (Dcs) in the tissue which upon LPS stimulation migrate to lung-draining LNs. The Gr1(int) cells were found to blunt the ability of the lung DCs to upregulate GATA-3 or to promote STAT5 activation in primed Th2 cells, both transcription factors having critical roles in TH2 effector function. Thus, a complete understanding of the generation and regulation of the Gr1(int) cells would provide new avenues to either promote or delete these cells for disease-specific immunoregulation.