Ian Lewkowich, PhD

Why Do Regulatory T Cells Not Work in People with Allergic Asthma?

A complex immune response is involved in asthma, and much is still not understood about this process. Dr. Lewkowich has focused his research on the role a specific cell, a “regulatory” T cell, or TReg, plays in preventing allergic asthma.

TRegs normally help control immune system responses before they become damaging. Tregs inhibit immune responses by acting on two main targets. By targeting other T cells, Tregs can inhibit existing immune responses, while targeting a second cell type, the dendritic cell, prevents the development of immune responses. Dr. Lewkowich found that mice that are susceptible to the development of an experimental form of asthma have many TRegs, but these TRegs do not function like those in mice without asthma.

Through an American Lung Association Senior Research Training Fellowship, Dr. Lewkowich hoped to find out whether the mice with asthma are not producing some substance needed to turn off the responses that cause asthma; whether the TRegs in asthmatic mice are normal, but other cells simply fail to see them, or a combination of the two.

He studied mice that were susceptible to asthma and those that were resistant to asthma, and found although exposure to allergens increased the production of certain substances by Tregs, there were no differences between the two sets of mice. However, when the ability of Tregs to act on another cell involved in the immune response, dendritic cells, was measured, Tregs (whether they came from asthma-susceptible, or asthma-resistant mice) successfully targeted dendritic cells from resistant mice, but not those from susceptible mice. This demonstrates that the defect lay in the ability of dendritic cells to respond to Tregs, not in the Tregs themselves. Further experimentation has revealed that a particular inhibitory pathway crucial for the ability of Tregs to target dendritic cells appears to be non-functional in the mice susceptible to asthma.

Experiments are currently underway to overcome this defect in asthma-susceptible mice, increasing their resistance to the development of allergic asthma.

Lewkowich, IP et al. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J. Exp. Med. (202): 1549-1561, 2005.

Kohl, J., Baelder, R., Lewkowich, IP. et al. A regulatory role for the C5a anaphylotoxin on type 2 immunity in asthma. J. Clin. Invest. (116): 783-796, 2006.

Rothenberg, MR., Doepker, MP, Lewkowich IP, et al. The cationic amino acid transporter 2 regulates inflammatory homeostasis in the lung. Proc. Nat. Acad. Sci. (103): 14895-14900, 2006

Lewkowich IP, et al. Enhanced allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice. PLoS ONE. (3): e3879, 2008

Zhang X, Lewkowich IP, al. A protective role for C5a in the development of allergic asthma associated with altered levels of B7-H1 and B7-DC on plasmacytoid dendritic cells. J. Immunol. (182): 5123-5130, 2009

Lewkowich IP, et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat. Immunol. (10): 928-935. 2010.