MAIT cell-directed therapy of Mycobacterium tuberculosis infection

Shunsuke Sakai,Keith D Kauffman,Sangmi Oh,Daniel L Barber,Christine E Nelson,Clifton E Barry

doi:10.1038/s41385-020-0332-4

Shunsuke Sakai, Keith D Kauffman + Show 4 more

Open Access

https://doi.org/10.1038/s41385-020-0332-4

Copy DOI

Abstract

Mucosal-associated invariant T (MAIT) cells are potential targets of vaccination and host-directed therapeutics for tuberculosis, but the role of MAIT cells during Mycobacterium tuberculosis (Mtb) infection in vivo is not well understood. Here we find that following Mtb infection MAIT cells mount minimal responses, and MAIT cell-deficient MR1−/− mice display normal survival. Preinfection expansion of MAIT cells through 5-OP-RU vaccination fails to protect against subsequent Mtb challenge. In fact, 5-OP-RU vaccination delays Mtb-specific CD4 T cell priming in lung-draining lymph nodes, and conversely MR1 deficiency or blockade accelerates T cell priming. The MAIT cell-mediated delay in T cell priming is partly dependent on TGF-β. Surprisingly, 5-OP-RU treatment during chronic infection drives MAIT cell expansion and an IL-17A-dependent reduction in bacterial loads. Thus, during early infection MAIT cells directly contribute to the notoriously slow priming of CD4 T cells, but later during infection MAIT cell stimulation may be an effective host-directed therapy for tuberculosis.

Highlights

Tuberculosis (TB) is the leading cause of death due to a single infectious agent[1]
200 Here we find that the endogenous Mucosal-associated invariant T (MAIT) cell response has little role in host resistance to Mycobacterium tuberculosis (Mtb) infection, and instead early MAIT cell responses impede the priming of conventional peptide-specific CD4 T cells
Endogenous MAIT cells do not contribute to host protection following Mtb infection To define the kinetics of MAIT cell responses in Mtb infection, mice were infected with Mtb and the frequency of MAIT cells in the lungs were assessed using MR1/5-OP-RU tetramers

Summary

Introduction

Tuberculosis (TB) is the leading cause of death due to a single infectious agent[1]. The only vaccine currently available for TB, Bacillus Calmette-Guérin (BCG), provides little protection from TB beyond infancy as currently utilized, and new vaccination strategies are greatly needed. Antitubercular chemotherapy is effective in treating infection with drug-susceptible strains of Mycobacterium tuberculosis (Mtb), but new approaches in treating. A better understanding of host-protective immune cells and molecules may provide insight into targets for the development of novel vaccines and treatments for TB. Mucosal-associated invariant T (MAIT) cells are a interesting potential target for TB vaccination and HDT. MAIT cells express a semi-invariant TCR specific for the riboflavin metabolite derivative 5-OP-RU presented by MR1. In support of their potential role in Mtb infection, MAIT cells are reduced in circulation and enriched in the airways of individuals with active TB disease compared to healthy donors[4,5,6].

Methods

Results

Conclusion