University of Massachusetts Medical School Faculty Publications

Title

Anti-IFN-gamma and peptide-tolerization therapies inhibit acute lung injury induced by cross-reactive influenza A-specific memory T cells

UMMS Affiliation

Department of Pathology

Date

3-15-2013

Document Type

Article

Medical Subject Headings

Acute Lung Injury; Animals; Antibodies; CD8-Positive T-Lymphocytes; Cell Line; Cricetinae; Cross Reactions; Disease Models, Animal; Epitopes, T-Lymphocyte; Humans; *Immune Tolerance; *Immunologic Memory; Influenza A virus; Interferon-gamma; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Male; Mice; Mice, Inbred C57BL; Orthomyxoviridae Infections; Peptide Fragments; Severity of Illness Index

Disciplines

Immunology of Infectious Disease | Respiratory Tract Diseases | Virus Diseases

Abstract

Viral infections have variable outcomes, with severe disease occurring in only few individuals. We hypothesized that this variable outcome could correlate with the nature of responses made to previous microbes. To test this, mice were infected initially with influenza A virus (IAV) and in memory phase challenged with lymphocytic choriomeningitis virus (LCMV), which we show in this study to have relatively minor cross-reactivity with IAV. The outcome in genetically identical mice varied from mild pneumonitis to severe acute lung injury with extensive pneumonia and bronchiolization, similar to that observed in patients who died of the 1918 H1N1 pandemic. Lesion expression did not correlate with virus titers. Instead, disease severity directly correlated with and was predicted by the frequency of IAV-PB1703- and IAV-PA224-specific responses, which cross-reacted with LCMV-GP34 and LCMV-GP276, respectively. Eradication or functional ablation of these pathogenic memory T cell populations, using mutant-viral strains, peptide-based tolerization strategies, or short-term anti-IFN-gamma treatment, inhibited severe lesions such as bronchiolization from occurring. Heterologous immunity can shape outcome of infections and likely individual responses to vaccination, and can be manipulated to treat or prevent severe pathology.

Rights and Permissions

Citation: J Immunol. 2013 Mar 15;190(6):2736-46. doi: 10.4049/jimmunol.1201936. Link to article on publisher's site

Related Resources

Link to Article in PubMed