Self-reactive CFTR T cells in humans: implications for gene therapy

Area of Science:

• Immunology
• Genetics
• Biochemistry

Background:

• Cystic fibrosis (CF) is a common, lethal autosomal recessive disorder with no current cure.
• Treatments focus on gene therapy and small-molecule drugs targeting CFTR mutations.
• Molecular therapies risk activating T cells against the wild-type CFTR protein.

Purpose of the Study:

• To validate the human interferon-γ enzyme-linked immunospot (ELISPOT) assay for analyzing CFTR-specific T cell responses.
• To assess T cell reactivity to CFTR in patients with CF and healthy individuals.

Main Methods:

• Validation of the human interferon-γ ELISPOT assay.
• Application of the assay to analyze CFTR-specific T cell responses.
• Testing samples from CF patients and non-CF subjects in the US and UK.

Main Results:

• The human interferon-γ ELISPOT assay was successfully validated.
• Low levels of self-reactive CFTR-specific T cells were found in non-CF subjects.
• CF patients exhibited a range of low to high levels of self-reactive CFTR-specific T cells.

Conclusions:

• The validated ELISPOT assay is a reliable tool for measuring CFTR-specific T cell immunity.
• Understanding these T cell responses is crucial for developing safe and effective CFTR-targeted therapies.
• The findings provide a baseline for immune monitoring in CF patients undergoing novel treatments.