Regulatory T Cell Inhibition of Natural Killer Cells in COPD

ABSTRACT
Chronic obstructive pulmonary disease (COPD) is a highly prevalent disorder that is primarily attributed to
smoking, and which disproportionately affects Veterans. New therapeutic approaches are needed as neither
current therapies nor smoking cessation halt the irreversible decline in lung function once initiated. The
chronic infiltration of inflammatory cells is a hallmark of COPD and results from both innate and adaptive
immune responses. Natural killer cells (NKs) are innate cells that have been shown to mediate rapid
cytotoxicity towards autologous lung epithelial cells in COPD. Our long-term goal is to understand whether we
can use an immunotherapy approach to suppress lung NK cytotoxicity against lung parenchyma without
compromising immune surveillance. To this end, regulatory T cells (Tregs) have been shown to suppress NKs
but Tregs are known to be decreased in COPD, suggesting that the loss of Tregs may be contributing to the
increased cytotoxicity of lung NKs in COPD. Our Central Hypothesis is that increasing Treg functionality will
block the cytotoxicity of lung NKs from COPD patients and will reduce NK-driven lung destruction in a murine
model of COPD. Our proposal will use human lung tissue and paired peripheral blood and an established
murine model of cigarette smoke exposure. Aim 1 will confirm the ability of circulating human Tregs to
suppress lung NK cytotoxicity in vitro and will determine whether this is limited to a specific Treg subset. After
confirming the potential for Tregs to modulate NKs, we will focus on addressing critical knowledge gaps
essential to designing trials of novel Treg therapies in COPD. The goal of Aim 2 will be to test the in vivo
effects of adoptively transferring Treg subsets into our murine model. Specifically, we will evaluate Treg
suppression of NKs and T cells and also determine how the inflammatory environment effects Treg phenotype,
stability, and migration. In Aim 3, we will focus on improving the stability of Tregs as they have been shown to
have functional plasticity when introduced to a proinflammatory environment. Increasing the stability of the
Tregs should also increase their long-term suppressive potential. We will conclude by testing the effects of our
optimized Treg therapy in a 6-month cigarette smoke exposure murine model and determine whether we can
halt progressive lung destruction. Successful completion of this project will provide crucial data, which are not
currently available, on the potential of Treg therapy to regulate NK cytotoxicity and treat COPD. There are
currently >280 ongoing clinical trials using Treg therapy for the treatment of autoimmune disease and organ
transplant, but there are no studies of Treg therapy in COPD.

Grant Number: 5I01CX001553-11
NIH Institute/Center: VA
Principal Investigator: Christine Basmajian