T cell responses to aerosolised antigen

Lee, Shiour-Ching (1999) T cell responses to aerosolised antigen. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

DO11.10 transgenic mice express an ovalbumin (OVA) specific αβ T cell receptor (TCR) which recognises the OVA_323-339 peptide presented by the I-A^d molecule and is identified by the KJ1-26 clonotypic antibody. We have used DO11.10 mice to study pulmonary T cell responses to inhaled aerosolised antigens by monitoring the inflammatory cells recruited to the lung, expression of cytokines, and the responses of T cells present in the lung tissue.

Exposure of DO11.10 mice to aerosolised OVA induced an increase in the number of eosinophils, macrophages (the latter of which were F4/80⁺ and M1/70⁺), and the expression of mRNA for IL-4, IFN-γ and TNF-α in the lung tissue. However, following aerosol challenge, T cell proliferative response to OVA_323-339 peptide or anti-CD3 was lost. The reduction in proliferative response was associated with the marked decrease of IL-2, but not the production of IFN-γ. The failure of the T cells to respond to antigen stimulation was a consequence of the actions of adherent interstitial macrophages expressing F4/80, M1/70, class II, CD80, CD86 and ICAM-1. Following restimulation with OVA_323-339 peptide in vitro, the cell cycle of the lung parenchymal T cells was arrested at G0/G1 phase. However, the removal of adherent macrophages or prevention of physical contact between them and the T cells resulted in the restoration of the proliferative responses. Moreover, the addition of exogenous IL-2 or the blocking of TGF-β, IL-4, IL-10, CTLA-4, nitric oxide or prostaglandin could not restore the proliferative responses. A neutralising Ab to IFN-γ was found to rescue T cell proliferative response, but this effect was gradually lost after repeated aerosol challenge. We also observed that epithelial cells regulated the proliferative responses of T cells by an E-cadherin dependent mechanism. In addition, CD8⁺ cells were involved in the attenuation of lung parenchymal T cells, but by a mechanism not involving Fas/Fas ligand.

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