CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature
Akul Singhania,
Paige Dubelko,
Rebecca Kuan,
William D. Chronister,
Kaylin Muskat,
Jyotirmoy Das,
Elizabeth J. Phillips,
Simon A. Mallal,
Grégory Seumois,
Pandurangan Vijayanand,
Alessandro Sette,
Maria Lerm,
Bjoern Peters,
Cecilia Lindestam Arlehamn
Affiliations
Akul Singhania
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
Paige Dubelko
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
Rebecca Kuan
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
William D. Chronister
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
Kaylin Muskat
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
Jyotirmoy Das
Division of Infection and Inflammation, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
Elizabeth J. Phillips
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA 6150, Australia; Vanderbilt University School of Medicine, Nashville, TN 37235, USA
Simon A. Mallal
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA 6150, Australia; Vanderbilt University School of Medicine, Nashville, TN 37235, USA
Grégory Seumois
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
Pandurangan Vijayanand
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
Alessandro Sette
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
Maria Lerm
Division of Infection and Inflammation, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
Bjoern Peters
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
Cecilia Lindestam Arlehamn
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Corresponding author.
Background: The century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity. Methods: We investigated immune responses in adult individuals pre and 8 months post BCG vaccination. We specifically determined changes in gene expression, cell subset composition, DNA methylome, and the TCR repertoire induced in PBMCs and CD4 memory T cells associated with antigen stimulation by either BCG or a Mycobacterium tuberculosis (Mtb)-derived peptide pool. Findings: Following BCG vaccination, we observed increased frequencies of CCR6+ CD4 T cells, which includes both Th1* (CXCR3+CCR6+) and Th17 subsets, and mucosal associated invariant T cells (MAITs). A large number of immune response genes and pathways were upregulated post BCG vaccination with similar patterns observed in both PBMCs and memory CD4 T cells, thus suggesting a substantial role for CD4 T cells in the cellular response to BCG. These upregulated genes and associated pathways were also reflected in the DNA methylome. We described both qualitative and quantitative changes in the BCG-specific TCR repertoire post vaccination, and importantly found evidence for similar TCR repertoires across different subjects. Interpretation: The immune signatures defined herein can be used to track and further characterize immune responses induced by BCG, and can serve as reference for benchmarking novel vaccination strategies.
