Mycobacterium tuberculosis-specific CD4 T cells expressing CD153 inversely associate with bacterial load and disease severity in human tuberculosis

Elsa Du Bruyn,Alan Sher,Robert J Wilkinson,Cecilia S Lindestam Arlehamn,Catherine Riou,Sheena Ruzive,Alessandro Sette,Daniel L Barber

doi:10.1038/s41385-020-0322-6

Abstract

Recent data from mice and non-human primate models of tuberculosis suggested that CD153, a TNF super family member, plays an important role in Mycobacterium tuberculosis (Mtb) control. However, this molecule has not been comprehensively evaluated in humans. Here, we show that the proportion of Mtb-specific CD4 T cells expressing CD153 was significantly reduced in active TB patients compared to latently infected persons. Importantly, the CD153+ Mtb-specific CD4 response inversely correlated with lung bacterial load, inferred by Xpert cycle threshold, irrespective of HIV status. Antitubercular treatment partially restored CD153 expression on Mtb-specific CD4 T cells. This is the first report of a subset of Mtb-specific CD4 T cells showing strong negative correlation with bacterial burden. Building on substantial evidence from animal models implicating CD153 as a mediator of host protection, our findings suggest it may play a similar role in humans and its measurement may be useful to evaluate TB vaccine efficacy.

Highlights

Tuberculosis (TB) remains the leading cause of death by infection worldwide with nearly 10 million new cases and about 1.5 million TB-related deaths in 2018.1 CD4 T-cell responses are critical for control of Mycobacterium tuberculosis (Mtb) infection, and HIV-infection-associated CD4 T-cell depletion greatly increases susceptibility to developing TB disease
A study in mice showed that CD153 (a molecule belonging to the tumor necrosis factor (TNF) super family, named CD30L or TNFSF8) expressed by CD4 T cells was necessary for Mtb control in the lung, independently of IFNγ.[7]
Darrah et al reported that intravenous BCG vaccination, which showed superior protection to Mtb challenge compared to intradermal or aerosol route of vaccination in non-human primate (NHP), induced a unique CD4 T cell response enriched with CD153 gene transcripts together with other genes associated with protection against TB, such as IFNγ and IL21R.8,9

Summary

Introduction

Tuberculosis (TB) remains the leading cause of death by infection worldwide with nearly 10 million new cases and about 1.5 million TB-related deaths in 2018.1 CD4 T-cell responses are critical for control of Mycobacterium tuberculosis (Mtb) infection, and HIV-infection-associated CD4 T-cell depletion greatly increases susceptibility to developing TB disease. (a molecule belonging to the tumor necrosis factor (TNF) super family, named CD30L or TNFSF8) expressed by CD4 T cells was necessary for Mtb control in the lung, independently of IFNγ.[7] complementary data from a non-human primate (NHP) Mtb infection model showed that the frequency of Mtb-specific CD4 T cells expressing CD153 inversely correlated with bacterial load in granulomas.[7] Further evidence supporting a role for CD153 in Mtb protection arose from a recent study assessing the protective potential of intravenous BCG immunization.[8] Darrah et al reported that intravenous BCG vaccination, which showed superior protection to Mtb challenge compared to intradermal or aerosol route of vaccination in NHPs, induced a unique CD4 T cell response enriched with CD153 gene transcripts together with other genes associated with protection against TB, such as IFNγ and IL21R.8,9

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