Identification of mycobacterial ribosomal proteins as targets for CD4+ T cells that enhance protective immunity in tuberculosis

Steven C. Kennedy, Alison J. Johnson, Sushma Bharrhan, Cecilia S.Lindestam Arlehamn, Jiayong Xu, Scott J. Garforth, John Chan, William R. Jacobs, Alessandro Sette, Steven C. Almo, Steven A. Porcelli

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Mycobacterium tuberculosis remains a threat to global health, and a more efficacious vaccine is needed to prevent disease caused by M. tuberculosis. We previously reported that the mycobacterial ribosome is a major target of CD4+ T cells in mice immunized with a genetically modified Mycobacterium smegmatis strain (IKEPLUS) but not in mice immunized with Mycobacterium bovis BCG. Two specific ribosomal proteins, RplJ and RpsA, were identified as cross-reactive targets of M. tuberculosis, but the breadth of the CD4+ T cell response to M. tuberculosis ribosomes was not determined. In the present study, a library of M. tuberculosis ribosomal proteins and in silico-predicted peptide libraries were used to screen CD4+ T cell responses in IKEPLUS-immunized mice. This identified 24 out of 57 M. tuberculosis ribosomal proteins distributed over both large and small ribosome subunits as specific CD4+ T cell targets. Although BCG did not induce detectable responses against ribosomal proteins or peptide epitopes, the M. tuberculosis ribosomal protein RplJ produced a robust and multifunctional Th1-like CD4+ T cell population when administered as a booster vaccine to previously BCG-primed mice. Boosting of BCGprimed immunity with the M. tuberculosis RplJ protein led to significantly reduced lung pathology compared to that in BCG-immunized animals and reductions in the bacterial burdens in the mediastinal lymph node compared to those in naive and standard BCG-vaccinated mice. These results identify the mycobacterial ribosome as a potential source of cryptic or subdominant antigenic targets of protective CD4+ T cell responses and suggest that supplementing BCG with ribosomal antigens may enhance protective vaccination against M. tuberculosis.

Original languageEnglish (US)
Article numbere00009-18
JournalInfection and Immunity
Volume86
Issue number9
DOIs
StatePublished - Sep 1 2018

Fingerprint

Ribosomal Proteins
Mycobacterium tuberculosis
Mycobacterium bovis
Immunity
Tuberculosis
T-Lymphocytes
Ribosomes
Vaccines
Large Ribosome Subunits
Small Ribosome Subunits
Mycobacterium smegmatis
Peptide Library
Computer Simulation
Libraries
Epitopes
Vaccination
Lymph Nodes
Pathology
Antigens
Lung

Keywords

  • Antigen
  • Cryptic
  • Mycobacteriology
  • Ribosome
  • T cells
  • Tuberculosis
  • Tuberculosis vaccines

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

Identification of mycobacterial ribosomal proteins as targets for CD4+ T cells that enhance protective immunity in tuberculosis. / Kennedy, Steven C.; Johnson, Alison J.; Bharrhan, Sushma; Arlehamn, Cecilia S.Lindestam; Xu, Jiayong; Garforth, Scott J.; Chan, John; Jacobs, William R.; Sette, Alessandro; Almo, Steven C.; Porcelli, Steven A.

In: Infection and Immunity, Vol. 86, No. 9, e00009-18, 01.09.2018.

Research output: Contribution to journalArticle

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