Myeloid cells immunomodulate tissue niches and promotes idiopathic pulmonary fibrosis

Abstract

Background: Despite the availability of pharmacologic therapies, idiopathic pulmonary fibrosis (IPF) is a clinical challenge. Robust evidence supports monocytes as biomarkers of progression in IPF. Yet, their precise role and specific myeloid subtypes is unknown.

Methods and Results: FACS from controls and IPF patients’ tissue (6 vs.10) and blood (32 vs. 79) analyzed myeloid subtypes abundance, e.g. MDSC and monocytes. We confirmed that M-MDSC is the more abundant circulating subset, and a gel invassion assay confirmed their strong invasiveness potential, compared to other subsets and controls in IPF. Immunostainings of primary IPF M-MDSC/fibroblast co-culture showed de-novo myofibroblast formation by upregulating α-SMA. We hypothesized that MDSC immunomodulation may lead to fibrosis, thus, we co-culture autologous MDSC with T cells to assess proliferation, exhaustion and T reg formation. Primary co-cultures showed decreased proliferation of CD8+ and CD4+ in IPF. We developed an in-vitro model to assess exhaustion, as is known known that exhausted T cells exhibit altered proliferation. Autologous co-cultures induced CD8+ T cell exhaustion (PD1-, Lag3+, Tim3+, TNFalpha-, INFg-), and preliminary data supports de-novo FoxP3 expression, creating a suppressive environment in IPF. Immunofluorescence confirmed the presence of CD8+ PD1+ T cells neiboring PDL-1+ MDSC in IPF tissue.

Conclusions: Circulating MDSC are present and increased in IPF patients, being M-MDSC the predominant subset. M-MDSC have high invasive potential, can induce myofibroblasts formation, suggesting an in-situ role. We proved that MDSC induces PD1+ cells and, CD8+ PD1+ T cell and PDL-1+ MDSC are present in IPF tissue, hinting, the regulation of a PD1-PDL1 axis, whose role in IPF needs to be determined