Rebecca Shilling, M.D.

The Role of CD28 Family Member Inducible Costimulator (ICOS) in the Development, Proliferation, and Effector Function of Th2 Cells in both Humans and Mice

Research Summary

1. ICOS Costimulation and the development of Th2-mediated disease in humans. 
In collaboration with Dr. Carole Ober, Dept. of Human Genetics, we have identified several polymorphisms in the promoter region of ICOS. Two variants proved to have an association with allergic sensitization and increased serum IgE in a founder population and to be associated with increased ICOS surface expression and a Th2 cytokine profile.  This work culminated in a first author paper in the Cutting Edge section of the Journal of Immunology in August 2005.  From this project, we hypothesized that the level of ICOS expression influences Th2 differentiation and the predisposition to allergy. 

The mechanisms of Th2 differentiation in vivo in humans are not well understood and a better understanding of the mechanisms responsible for the development of Th2 immunity may lead to novel therapies for diseases like asthma. In our study we found that individuals that expressed more ICOS on their T cells produced more Th2 cytokines upon stimulation in vitro. By recruiting a cohort of individuals with asthma and allergy, we are studying whether humans with Th2 disease express more ICOS and as a result have increased Th2 cytokine production.  In addition an important aim of this study is to determine the mechanisms by which the level of ICOS costimulation may affect Th2 cytokine secretion from allergic individuals and controls.

2. ICOS Costimulation and Th2 development in vivo in a murine model of allergic airway disease. 
While costimulation has been studied in terms of CD28 and more recently ICOS, it has only been studied in vivo as a signal that is present or absent.  However, we found that increased ICOS surface expression on human T cells correlated with increased Th2 cytokine production from peripheral blood mononuclear cells.  Based on this work, we have been investigating the hypothesis that the level of expression of the costimulatory molecule, ICOS, affects Th2 immunity in vivo. 

To test the hypothesis, we have taken advantage of the finding that mice heterozygous for the ICOS gene, ICOS+/- , express 50% less ICOS on resting T cells compared to wild-type ICOS+/+ littermates.  In our mouse model of allergic airway disease, we have found that the level of ICOS expression in these mice affects BAL airway eosinophilia and Th2 cytokine production in the lungs and mediastinal lymph nodes.  This work has been submitted to the Journal of Immunology.  Interestingly, the most dramatic effect of decreased ICOS expression is on serum IgE levels.  This data correlates with my findings in humans and further supports a major role for ICOS in the susceptibility to allergic sensitization. 

3. ICOS and CD28 in humoral immunity. 
CD28 has long been known to be the costimulatory molecule necessary for Th2-mediated immunity.  However, my studies above, as well as studies from other groups have demonstrated an important role for ICOS in these responses.  Since ICOS is a potent inducer of Th2 cytokines and I have found an association with allergy and IgE, I investigated if ICOS played a role in vivo independent of CD28 in Th2 immunity.  I found that while ICOS was expressed in the absence of CD28, Th2-mediated inflammation was not induced in CD28-/- mice upon stimulation of ICOS with a soluble form of its ligand, B7RP-1-Fc.  However, I did find that ICOS-/- mice have a significant defect in airway eosinophilia, isotype switching to IgG1 and IgE, as well as germinal center formation.  Interestingly, increased CD28 costimulation only partially augmented Th2 immune responses in the absence of ICOS and did not completely rescue serum IgE levels, germinal center formation or the expansion of CD4+CXCR5+ follicular B helper T cells (TFH).  Thus CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo. 

Selected Papers