Mucosal Vaccination with Cyclic Dinucleotide Adjuvants Induces Effective T Cell Homing and IL-17-Dependent Protection against Mycobacterium tuberculosis Infection

J Immunol. 2022 Jan 15;208(2):407-419. doi: 10.4049/jimmunol.2100029. Epub 2021 Dec 29.


Tuberculosis consistently causes more deaths worldwide annually than any other single pathogen, making new effective vaccines an urgent priority for global public health. Among potential adjuvants, STING-activating cyclic dinucleotides (CDNs) uniquely stimulate a cytosolic sensing pathway activated only by pathogens. Recently, we demonstrated that a CDN-adjuvanted protein subunit vaccine robustly protects against tuberculosis infection in mice. In this study, we delineate the mechanistic basis underlying the efficacy of CDN vaccines for tuberculosis. CDN vaccines elicit CD4 T cells that home to lung parenchyma and penetrate into macrophage lesions in the lung. Although CDNs, like other mucosal vaccines, generate B cell-containing lymphoid structures in the lungs, protection is independent of B cells. Mucosal vaccination with a CDN vaccine induces Th1, Th17, and Th1-Th17 cells, and protection is dependent upon both IL-17 and IFN-γ. Single-cell RNA sequencing experiments reveal that vaccination enhances a metabolic state in Th17 cells reflective of activated effector function and implicate expression of Tnfsf8 (CD153) in vaccine-induced protection. Finally, we demonstrate that simply eliciting Th17 cells via mucosal vaccination with any adjuvant is not sufficient for protection. A vaccine adjuvanted with deacylated monophosphoryl lipid A (MPLA) failed to protect against tuberculosis infection when delivered mucosally, despite eliciting Th17 cells, highlighting the unique promise of CDNs as adjuvants for tuberculosis vaccines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • CD30 Ligand / metabolism
  • Interferon-gamma / immunology
  • Interleukin-17 / immunology*
  • Lung / cytology
  • Lung / immunology
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium tuberculosis / immunology*
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / immunology
  • Th17 Cells / immunology*
  • Tuberculosis Vaccines / immunology*
  • Tuberculosis, Pulmonary / immunology
  • Tuberculosis, Pulmonary / prevention & control*
  • Vaccination


  • Adjuvants, Immunologic
  • CD30 Ligand
  • IFNG protein, mouse
  • Il17a protein, mouse
  • Interleukin-17
  • Tnfsf8 protein, mouse
  • Tuberculosis Vaccines
  • Interferon-gamma