There is a strong body of evidence that the sensitivity to allergies, such as asthma, results from a dysregulation of immune responses in early life. This obliges us to better understand early life immune responses, and in particular, the expression of interferon gamma (IFN gamma), a cytokine with the capacity to down-regulate allergic T cell responses. We have recently shown that in early life, unconventional T cells, in particular gamma delta cells, are an important source of IFN gamma, and that young mice depend on such cells for primary protection against mucosal infection. Therefore, it is logical to ask whether the experimental up-regulation of unconventional T cells in early life will promote IFN gamma production that will alter the susceptibility to allergy. To accomplish this, mice will be infected with a natural gut pathogen that activates gamma delta cells, and their susceptibility then assessed to food allergy, and to airway hypersensitivity. The gut, rather than the lung, has been chosen as the primary target of unconventional T cell activation because the appropriate natural infection system is in place. In short, the first aim of the application is a proof of principle. Nevertheless, should the protocol successfully regulate allergy, it will lay an important foundation to attempt to regulate unconventional T cells directly in the lung (which is beyond the scope of this application) or to use non-infectious protocols to regulate unconventional T cells more globally, which is the subject of Aims 2 and 3. Although the immune systems of young mice and human children differ in their states of maturity, data are presented that show the relevance of human gamma delta cells to the production of IFN gamma in early life. Thus, Aim 4 will examine the degree to which the strategies that we develop in the animal model may be practically applied to humans.
| Gibbons, D L; Haque, S F Y; Copestake, S L et al. (2009) Suppression of airway inflammation by a natural acute infection of the intestinal epithelium. Mucosal Immunol 2:144-55 |
