Blake, Judith A., Seifert, Julia, Miranda-Hernandez, Socorro, Ruscher, Roland, Giacomin, Paul R., Doolan, Denise L., and Kupz, Andreas (2025) Distal airway epithelial progenitors mediate TGF-β release to drive lung CD8+ TRM induction following mucosal BCG vaccination. Mucosal Immunology. (In Press)

Preview

PDF (Accepted Publisher Version) - Accepted Version Available under License Creative Commons Attribution. Download (19MB) | Preview

Abstract

A principal reason for the high global morbidity and mortality of tuberculosis (TB) is the lack of efficacy of the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG), as intradermal BCG does not induce local pulmonary immune memory. Animal studies have shown that inhalation of BCG vaccination provides superior mucosal protection against TB due to generation of lung resident memory T cells (TRM). Here, we demonstrated that following mucosal vaccination with the genetically modified more virulent BCG strain, BCG::RD1, distal airway epithelial progenitors were mobilized to assist with restoration of alveolar epithelium. By way of their integrin-mediated activation of latent TGF-β, lung CD8+ TRM differentiation was induced. Mucosal vaccinations using nonvirulent strains of BCG in which airway epithelial progenitors were not mobilized, as well as genetic inhibition of integrin-mediated activation of TGF-β, resulted in significantly lower numbers of lung CD8+ TRM with subsequent reduced protection against Mycobacterium tuberculosis (Mtb)-induced lung pathology in mice. The results link airway epithelial progenitor-mediated repair of injured lung tissue with a role in the induction of resident CD8+ T cell memory. These findings provide further explanation why mucosal vaccination with virulent BCG strains is more protective against TB and thus has implications for future TB vaccine development.

Item ID:	86517
Item Type:	Article (Research - C1)
ISSN:	1935-3456
Copyright Information:	© 2025 The Author(s). Published by Elsevier Inc. on behalf of Society for Mucosal Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Funders:	National Health and Medical Research Council of Australia (NHMRC)
Projects and Grants:	NHMRC Investigator grant GNT2008715, NHMRC Ideas grant GNT2001262
Date Deposited:	05 Aug 2025 03:20
FoR Codes:	31 BIOLOGICAL SCIENCES > 3107 Microbiology > 310702 Infectious agents @ 30% 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320404 Cellular immunology @ 30% 32 BIOMEDICAL AND CLINICAL SCIENCES > 3207 Medical microbiology > 320701 Medical bacteriology @ 40%
SEO Codes:	28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280103 Expanding knowledge in the biomedical and clinical sciences @ 100%
Downloads:	Total: 1 Last 12 Months: 1
	More Statistics