BCG vaccination induces antibacterial effector functions among Vδ1/3 T cells that are associated with protection against tuberculosis

Megan D Maerz; Mohau S Makatsa; Allison N Bucsan; Matthew S Sutton; Emma Bishop; Ziwei Tian; Erik D Layton; Mario Roederer; Alex K Shalek; Robert A Seder; Thomas J Scriba; Chuangqi Wang; Patricia A Darrah; Chetan Seshadri

doi:10.1016/j.xcrm.2025.102536

BCG vaccination induces antibacterial effector functions among Vδ1/3 T cells that are associated with protection against tuberculosis

Cell Rep Med. 2026 Jan 20;7(1):102536. doi: 10.1016/j.xcrm.2025.102536. Epub 2026 Jan 12.

Authors

Affiliations

¹ Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA; Molecular Medicine and Mechanisms of Disease Program, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
² Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
³ Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Biostatistics and Informatics, The Colorado School of Public Health, Aurora, CO 80045, USA.
⁵ Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
⁶ South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town 7935, South Africa.
⁷ Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
⁸ Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Electronic address: seshadri@uw.edu.

Abstract

γδ T cells expressing a Vδ1/3+ T cell receptor are enriched at mucosal surfaces, but their role in protection against Mycobacterium tuberculosis (Mtb) is largely unknown. We used multimodal single-cell RNA sequencing, mass cytometry, and flow cytometry to profile γδ T cells from human infants and macaques after protective vaccination with Mycobacterium bovis bacillus Calmette Guerin (BCG). A subset of Vδ1/3 T cells in BCG-vaccinated human infants shows evidence of clonal expansion and differentiation into Mtb-reactive cytotoxic effector cells. In macaques, intravenous BCG induces pro-inflammatory and cytotoxic responses to Mtb among Vδ1/3 T cells that are enriched in the airway compared to the blood. Finally, the frequency of cytokine-expressing Vδ1/3 T cells in the airway is associated with protection against Mtb challenge. Thus, Vδ1/3 T cells are activated by BCG and accumulate in the lung, where they upregulate cytotoxic and pro-inflammatory functions that may contribute to protective immunity against Mtb.

Keywords: BCG vaccine; Mycobacterium tuberculosis; T cell; T cell receptor; correlate of protection; cytotoxic T cell; gamma delta; human; rhesus macaque; tuberculosis.

MeSH terms

Animals
BCG Vaccine* / immunology
Cytokines / metabolism
Humans
Infant
Lung / immunology
Lung / microbiology
Macaca mulatta
Male
Mycobacterium bovis / immunology
Mycobacterium tuberculosis* / immunology
Receptors, Antigen, T-Cell, gamma-delta* / immunology
Receptors, Antigen, T-Cell, gamma-delta* / metabolism
T-Lymphocytes / immunology
Tuberculosis* / immunology
Tuberculosis* / prevention & control
Vaccination*

Substances

BCG Vaccine
Receptors, Antigen, T-Cell, gamma-delta
Cytokines