There is a plethora of literature demonstrating roles for CD4+ and CD8+ T cells, B cells, and dendritic cells as well as innate immune cells, in the development of allergic airway disease (AAD). Emerging data demonstrates the differential capabilities of these immune cells in terms of being pro- and/or anti-inflammatory at various stages of the disease process. The role of "suppressor" CD8+ T cells in AAD is controversial;multiple studies suggest both pro- and anti-inflammatory effects in various animal models and in human asthmatics. We have established a unique biphasic model of ovalbumin (OVA)-induced AAD, which with chronic OVA exposure results in resolution of AAD and the development of local inhalational tolerance (LIT). We have used this model to elucidate cellular involvement in basic pathogenic mechanisms regulating the development of AAD and also to investigate the regulatory mechanisms establishing LIT. We have shown that shifts in CD4+ T cells, B cells, and in particular, OVA specific CD8+ T cells, occur in various local lung compartments but not in systemic compartments at various stages of the model. These shifts correlate with differences in surface marker phenotype and in vivo and in vitro function of the cell types. This model puts us in a unique position to investigate the mechanistic role of each of these cell types and to help clarify the discrepancies between pro- and anti-inflammatory roles. These novel observations and additional preliminary data lead us to hypothesize that pro-inflammatory CD8+ T cells at AAD are replaced (i.e., clonal expansion or differentiation) in lung tissue by regulatory CD8+ T cells, which are dependent on B cells to present Ag via a MHC-I CD94/NKG2A - Qa-1 signaling system. We further hypothesize that this occurs only in lung tissues and that these regulatory CD8+ T cells play a requisite role in the resolution of AAD and the long term maintenance of airway homeostasis. Our overall objective is to determine the functional role of CD8+ T cells in the induction and resolution of AAD and the development of LIT. We anticipate that these studies will clarify homeostatic mechanisms of a complex regulatory pathway involving CD8+ Tregs, Bregs, and CD4+ Tregs. Moreover, we believe that the development of tertiary ectopic lymphoid tissue is essential for the local concentration of regulatory cells thereby promoting their interactions. The following Specific Aims address this hypothesis.
Aim 1. To demonstrate that CD8+ T cells are functionally altered during the progression from AAD to LIT and that this response is localized to cells in respiratory (hilar lymph node, lung tissue, bronchoalveolar lavage fluid) as compared to systemic (inguinal lymph node, spleen) tissue compartments: a. surface marker expression and cytokine profiles, b. in vivo functional assessments using adoptive transfers and depletion studies, c. co-localization and trafficking using confocal microscopy and chemokine influence.
Aim 2. Dependence of LIT on CD8+ T cells and the MHC I CD94/NKG2A - Qa-1 signaling system - in vivo and in vitro approaches.
Most animal models of asthma focus on its development and prevention;such studies are relevant but they do not specifically apply to the millions of patients with already established disease. We are investigating a different process, whereby mice are naturally able to recover from asthma, establish tolerance and restore normal airway homeostasis. This murine process may be representative of the beneficial human response to immunotherapy or it may represent how many children are able to outgrow their asthma. The identification of mechanisms underlying this process in mice may have clinical implications for the resolution of asthma in human subjects.
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