T Cells Primed by Live Mycobacteria Versus a Tuberculosis Subunit Vaccine Exhibit Distinct Functional Properties

EBioMedicine. 2018 Jan;27:27-39. doi: 10.1016/j.ebiom.2017.12.004. Epub 2017 Dec 7.

Abstract

Despite inducing strong T cell responses, Mycobacterium tuberculosis (Mtb) infection fails to elicit protective immune memory. As such latently infected or successfully treated Tuberculosis (TB) patients are not protected against recurrent disease. Here, using a mouse model of aerosol Mtb infection, we show that memory immunity to H56/CAF01 subunit vaccination conferred sustained protection in contrast to the transient natural immunity conferred by Mtb infection. Loss of protection to re-infection in natural Mtb memory was temporally linked to an accelerated differentiation of ESAT-6- and to a lesser extent, Ag85B-specific CD4 T cells in both the lung parenchyma and vasculature. This phenotype was characterized by high KLRG1 expression and low, dual production of IFN-γ and TNF. In contrast, H56/CAF01 vaccination elicited cells that expressed low levels of KLRG1 with copious expression of IL-2 and IL-17A. Co-adoptive transfer studies revealed that H56/CAF01 induced memory CD4 T cells efficiently homed into the lung parenchyma of mice chronically infected with Mtb. In comparison, natural Mtb infection- and BCG vaccine-induced memory CD4 T cells exhibited a poor ability to home into the lung parenchyma. These studies suggest that impaired lung migratory capacity is an inherent trait of the terminally differentiated memory responses primed by mycobacteria/mycobacterial vectors.

Keywords: Lung homing; M. tuberculosis; Natural immunity; T cell priming & differentiation; Vaccination.

MeSH terms

  • Animals
  • Antigens, Bacterial / immunology
  • Bacterial Proteins / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Differentiation
  • Cross-Priming / immunology*
  • Female
  • Immunologic Memory
  • Interleukin-17 / biosynthesis
  • Interleukin-2 / biosynthesis
  • Lung / microbiology
  • Lung / pathology
  • Male
  • Mice, Inbred C57BL
  • Mycobacterium tuberculosis / immunology*
  • T-Lymphocytes / immunology*
  • Tuberculosis / immunology*
  • Tuberculosis / microbiology*
  • Tuberculosis / prevention & control
  • Tuberculosis Vaccines / immunology*
  • Vaccines, Subunit / immunology*

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • ESAT-6 protein, Mycobacterium tuberculosis
  • Interleukin-17
  • Interleukin-2
  • Tuberculosis Vaccines
  • Vaccines, Subunit