VIRUS INFECTION AND T CELL DIFFERENTIATION IN ASTHMA

Yale University, New Haven CT

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Abstract

The relationship between virus infections and increased asthma flares in childhood is incompletely understood. It is now generally accepted that the predominant immune response in atopic asthma is mediated by T cells of the helper subtype (Th2). The following findings are important to note in the context of virus infections and asthmatic exacerbations in children: 1) An early pattern of transient Th2 response occurs in all neonates. This early Th2 bias eventually terminates in most individuals but persists in a significant fraction through adulthood. 2) Wheezing children over 2 years of age frequently have a combination of allergen- specific IgE (a Th2 response) and culture-proven virus infection. 3) In experimental animals, interleukin-4 (IL-4), a Th2-cell-derived cytokine, can convert cytotoxic CD8+T cells into non-toxic Th2-cytokine (IL-5) producing CD8+ T cells. We have recently established that the transcription factor GATA-3 plays a determinative role in Th2-specific gene expression. Also, in collaborative studies with us, Dr. Q. Hamid's group has demonstrated a significant increase in expression of GATA-3 mRNA colocalizing with IL-5 message in human asthmatic bronchoalveolar lavage (BAL) cells and biopsies compared to controls. Taken together, these observations lead us to hypothesize that: a) Viruses cause exacerbations of asthma by augmenting pre-existing Th2 responses through an increase in GATA-3 gene expression. b) Virus-induced increase in expression of the eosinophilic chemoattractant RANTES, which has been shown to activate T cells to trigger IL-5 production, also contributes to increased asthma flares during virus infections. To address this hypothesis we will: Aim I. Investigate the expression of GATA-3, T cell cytokine and RANTES mRNA in purified peripheral blood T cells of children by quantitative RT-PCR techniques. Aim II. Determine the consequence of T cell-specific expression of a dominant-negative mutant of GATA-3 on airway inflammation in mice using a doxycycline (dox)-inducible transgenic system recently established in our laboratory. These studies will determine whether inhibition of GATA-3 activity alone can abrogate Th2-like responses in vivo. Aim III. Determine the consequence of lung-specific inducible RANTES overexpression on T cell activation in vivo in transgenic mice. The effect of RANTES overexpression on GATA-3 and IL-5 gene expression will be investigated in T cells isolated from BAL cells and lung draining lymph nodes.