Biology subjects

Pavord, I. D.

Publications and source records attributed to Pavord, I. D..

3 recordsLinked to original sources

bioRxiv2020

Epithelial Cell Regulation of Type 2 Cytokine Release by Peripheral Blood Mononuclear Cells

BackgroundType 2 cytokines such as IL-13 and IL-5 are important drivers of pathophysiology and exacerbation in asthma. Defining how these type 2 cytokine responses are regulated is a research priority. Epithelial cells promote type 2 responses by releasing alarmins including IL-25, IL-33 and TSLP, but much less is known about inhibitory factors. MethodsIL-13 release was measured from peripheral blood mononuclear cells (PBMC) cultured with Interleukin (IL)-2 for five days. Epithelial cell lines or human bronchial epithelial cells (HBEC) isolated from healthy or asthma donors were added to these PBMC cultured with IL-2 and release of IL-13 or IL-5 measured. To characterise the mechanisms, we assessed the effect of mechanical disruption of epithelial cells, addition of the COX inhibitor indomethacin and the G-protein inhibitor pertussis toxin. ResultsPBMC cultured with IL-2 secreted type 2 cytokines in a cell number and time dependent manner. Epithelial cell lines inhibited IL-13 and IL-5 release after co-culture with PBMC in the presence of IL-2, directly, across a transwell and using epithelial cell supernatant. Cells or supernatant from HBEC from healthy or asthma donors also inhibited the cytokine release. Trypsin treatment of conditioned media indicated that inhibitory factor(s) are trypsin insensitive. Mechanical disruption of epithelial cells or indomethacin treatment had no effect, but pertussis toxin reduced epithelial cell inhibition of IL-2 driven type 2 cytokine release. ConclusionEpithelial cells regulate cytokine release by soluble factor(s) and this could be an important immunoregulatory function of the airway epithelium.

immunology↗

bioRxiv2020

Identification of lactate as a potential inhibitory factor within epithelial cell supernatant and its effects on type 2 T cell populations

Abstract / Short SummaryEpithelial cells have been shown previously to inhibit release of type 2 cytokines from T cells and this process could be important in a type 2-mediated diseases such as asthma. Factors secreted by epithelial cells could regulate inflammatory responses and release an all is well signal such that the immune system is controlled. Here we show that lung epithelial cells are able to inhibit IL-2 driven type 2 cytokine release by PBMC cells across a transwell indicating the involvement of soluble mediators. We then fractionate the mediators within the conditioned media using methanol chloroform separation and size fractionation. Inhibitory activity was demonstrated within the polar fraction of supernatant separated by methanol chloroform extraction. We then found that lactate, a component within the polar fraction was able to mediate inhibition of the type 2 cytokines. The inhibitory activity of lactate deserves further study and could play a role in the inhibition of T cell derived cytokines in vivo.

immunology↗

bioRxiv2018

Type-2 CD8+ T lymphocytes responsive to PGD2 and LTE4 in severe eosinophilic asthma

The functions and in vivo roles of type-2 CD8+ T cells in humans have not been well defined and this cell type has been largely overlooked in models of disease. We investigated this in the context of severe asthma with persistent airway eosinophilia - a phenotype associated with high exacerbation risk and responsiveness to type-2 cytokine-targeted therapies. In two independent cohorts we show that, in contrast to Th2 cells, type-2 cytokine-secreting CD8+CRTH2+ (Tc2) cells are enriched in blood and airways in severe eosinophilic asthma. Concentrations of prostaglandin D2 (PGD2) and cysteinyl leukotriene E4 (LTE4) are also increased in the airways of the same group of patients. In vitro PGD2 and LTE4 function synergistically to trigger Tc2 cell recruitment and activation in a TCR-independent manner. These lipids regulate diverse genes in Tc2 cells inducing type-2 cytokines and many other pro-inflammatory cytokines and chemokines which could contribute to eosinophilia. These findings are consistent with an important innate-like role for human Tc2 cells in severe eosinophilic asthma and suggest a potential target for therapeutic intervention in this and other diseases.

immunology↗