Title

Phenotypic and Functional Plasticity in the Endogenous CD8+ T cell Response Correlates with the Establishment and Resolution of Allergic Airway Disease

Date of Completion

January 2011

Keywords

Biology, Microbiology|Biology, Histology|Health Sciences, Immunology

Degree

Ph.D.

Abstract

There is a plethora of literature demonstrating important roles for CD4 + and CD8+ T cells, B cells, and dendritic cells (DC) as well as innate immune cells, both in the development of allergic airway disease (AAD) and in its regulation. New emerging studies demonstrate the differing functional capabilities of CD4+ and CD8+ T cells and B cells in terms of displaying a pro-inflammatory phenotype during the acute developmental stages of allergic airway disease (AAD) but possessing a regulatory phenotype in the later resolving or remodeling stage of the process. The role of CD8+ T cells in AAD is controversial, in that multiple studies demonstrate both pro-inflammatory and anti-inflammatory effects in various animal models and in humans with asthma. We have developed a spontaneous biphasic progression model of acute ovalbumin (OVA)-induced AAD, which with long term OVA exposure results in resolution of AAD and the development of what we have termed local inhalational tolerance (LIT). We hypothesize that: changes in the lung microenvironment promote CD8+ T cell plasticity, allowing for pro-inflammatory CD8+ T cells at AAD and anti-inflammatory (regulatory) CD8+ T cells at LIT. Here we have utilized this biphasic model to examine the endogenous antigen-specific CD8 + T cell response. This thesis is highlighted by several key findings: 1) Multiple systemic sensitizations result, as anticipated, in the step-wise augmentation of antigen specific antibody responses but unexpectedly after an initial boost resulted in a reduced endogenous antigen specific CD8 + T cell response. 2) A robust antigen-specific CD8+ T cell response was initiated to inhaled antigen in the local lung compartments at AAD and LIT. The response was reserved to the local lung compartments and was not identified in the systemic tissues. 3) For the first time the development of tertiary ectopic lymph tissue (TELT) in lung has been identified in a model of AAD and shown to associate with antigen-specific CD8+ T cells, through confocal microscopy. 4) Functional (IFN-γ and granzyme B production) and phenotypic, (NKG2A) changes in the lungs at AAD and LIT, are suggestive of CD8+ T cell plasticity. 5) The CD8 + T cell response at sensitization and during AAD and LIT was dominated by non-terminally differentiated MPEC and EEGs effector/memory cells which were demonstrated to still be responsive to re-exposure of OVA in discontinuous models of AAD. Thus we feel we have confirmed CD8+ T cell plasticity which could explain the contradictions in the literature. ^