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Role of a Critical Cell Surface Molecule in Tobacco-induced Lung Immune Cell Trafficking

Institution: Palo Alto Veterans Institute For Research
Investigator(s): Eugene Butcher, M.D.
Award Cycle: 2018 (Cycle 27) Grant #: 27IR-0054 Award: $1,002,925
Subject Area: Pulmonary Disease
Award Type: High Impact Research Project Award

Initial Award Abstract

Immune cells (white blood cells), including the T cells that carry immunity or cause inflammatory diseases, must migrate from the blood into tissues in order to be effective.  This ‘recruitment’ into tissues is mediated through a process called homing or trafficking, and chemoattractant molecules play an important role in this process.

Immune cell trafficking to the lung is poorly understood, and the impact of tobacco on immune cell trafficking to lung and other internal organs remains largely unknown. While smoking is implicated in lung inflammation, paradoxically it is beneficial in chronic inflammation of the gut. The cellular and molecular basis of these diverse effects remains unclear and will be addressed in our proposal.

GPR15 is a molecule present on the surface of T cells that enables them to traffic to certain organs.  GPR15 is highly upregulated in T cells of smokers: indeed, the frequency of GPR15+ cells in blood is an excellent biomarker of smoking exposure. We discovered Gpr15 expression in gut- and lung- T cells and showed GPR15-dependent T cell homing to gut.  Moreover, GPR15 positively or negatively regulates gut inflammation in different experimental models. We have now identified a molecule (GPR15L) present in the lining of internal organs that attracts GPR15-expresssing cells and have shown enhanced migration to GPR15L by T cells from smokers. 

We hypothesize a) that GPR15 and GPR15L help control lung immune cell trafficking; b) that tobacco-induced upregulation of GPR15 alters the trafficking of specific T cell subsets to lung and other internal organs including the gut; and c) that these alterations influence tobacco-evoked lung inflammation and contribute to protective effects of smoking in gut inflammation. 

To test these hypotheses, we will define the T cell subsets that upregulate GPR15 in smokers and assess their migration to GPR15L. We will also investigate mechanisms underlying GPR15 induction on T cells, focusing on major known molecular pathways of smoking-induced immune regulation, including the role of nicotine itself. Furthermore, we will use mouse models of disease to investigate the role of GPR15-GPR15L in T cell recruitment to the lung and in lung inflammation, and also in the modulation of lung and gut inflammation by tobacco-related pathways and smoking. The project will advance our understanding of tobacco’s influence on lung immune cell trafficking and modulation of lung and gut immune pathologies.