The broad, long-term objective of this proposal is to define the role of gammadelta T cells in the regulation of airway reactivity. This regulation is of vital importance during diseases that are associated with airway hyperresponsiveness (AHR), but the underlying mechanisms are still poorly understood. In a murine model of allergic AHR, we have found that gammadelta T cells regulate airway responsiveness, and that one particular subset suppresses and another promotes AHR. These subsets differ by their expression of TCR-Vy, but it is not yet clear how they control airway responsiveness. Because we have found that gammadelta T cells including the AHR-suppressive subset are in contact with dendritic cells (DC) within the lung, I hypothesize that specific interactions of DC with the two already identified gammadelta T cell subsets determine the AHR-regulatory influence of the gammadelta T cells. Therefore, I plan to characterize the AHR-regulatory 75 T cell populations, to define and compare the nature of their interactions with the DC, and to assess the consequences of these interactions for AHR and airway inflammation. Specifically, I propose: 1. To delineate key features of y5 T-cell-populations known to influence airway responsiveness. We will examine details of their responses to OVA-sensitization and challenge, and test, with regard to the two AHR-regulatory gammadelta T cell subsets and at the level of gene expression, our hypothesis that TCR-Vy-defined gammadelta cell-subsets are functionally different. 2. To define the cellular interactions that form the basis for AHR-regulation by gammadelta T cells. We will test the idea that gammadelta T cells continuously monitor DC in the lung, and whether monitoring involves the formation of immunological synapses with the DC. We will test whether DC induce AHR-regulatory competence in the gammadelta T cells, and whether the 75 T cells direct functional differentiation of the DC, with the predicted consequences for AHR. In the case of Vy4 + cells, we will test whether their alveolar epithelial environmenttheir functions, and in the case of VyI + cells, whether they promote allergen-responsive aB T cells. 3. To characterize molecular mechanisms involved in AHR-regulation by gammadelta T cells. We will pinpoint already identified requirements in the negative regulation of AHR by Vy4 + gammadelta T cells, namely expression of the peptide transporter TAP-l, and TNF-a. We will examine the significance of these requirements with regard to ligand recognition and activation of the gammadelta T cells, and with regard to their interaction with DC.
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