CD4+ T Cell Mechanisms of Cross-Protective Rhinovirus Immunity and Rhinovirus-Induced Allergic Asthma 278 views

Human rhinovirus (RV) is the major cause of the common cold, and poses a significant public health burden. RV infection also triggers acute wheezing episodes in patients with allergic asthma that often result in hospitalization. Despite this, there are no effective treatments or vaccines for RV infection. Little is known about CD4+ T cell responses induced by RV or the T cell mechanisms underlying virus-induced asthma. The overarching objective of this thesis is to define the nature of CD4+ T cell responses to RV in health and allergic asthma by precisely tracking T cells in a human experimental RV infection model using novel peptide/MHCII tetramers. The data show that circulating RV-specific CD4+ T cells in healthy uninfected subjects recognize immunodominant epitopes of RV capsid proteins that are conserved across multiple RV strains. These cells bear an activated TH1 effector memory signature, express CCR5, and respond rapidly to infection, consistent with cross-strain immunosurveillance. Moreover, increased numbers of RV-specific T cells prior to infection are linked to decreased infection rates. By contrast, higher numbers of circulating RV-specific TH1 cells relate to worse lung function in uninfected allergic asthmatics. During infection, RV triggers an augmented RV-specific TH1 response, along with other hallmark components of a type 1 response in the blood and airways. These findings challenge the prevailing views of deficient anti-viral responses in RV-induced asthma. We conclude that, although RV-specific TH1 responses control infection in health, unconstrained TH1 responses are linked to asthma pathogenesis despite underlying type 2 inflammation, even in the absence of infection. The findings support a model wherein repeated viral exposures increase the inflammatory set point in allergic asthma via TH1-mediated processes.

PHD (Doctor of Philosophy)

CD4+ T Cells; Rhinovirus; Allergic Asthma; Immunology

English

All rights reserved (no additional license for public reuse)

2018-11-05