Abstract
Author SummaryAbout one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), yet thanks to a robust immune response most infected people remain healthy. CD8 T cells are unique in detecting intracellular infections. Surprisingly, Mtb-reactive CD8 T cells are found in humans with no prior exposure to Mtb. We show that mucosal associated invariant T (MAIT) cells, which have no previously known in vivo function, make up a proportion of these Mtb-reactive CD8 T cells and detect Mtb-infected cells via a specific major histocompatibility molecule called MHC-related molecule 1, which is evolutionarily conserved among mammals. Mtb-reactive MAIT cells are enriched in lung and detect primary Mtb-infected lung epithelial cells from the airway where initial exposure to Mtb occurs. We go on to show that MAIT cells are not specific for Mtb since they can detect cells infected with a variety of other bacteria. Curiously, Mtb-reactive MAIT cells are absent in the blood of individuals with active tuberculosis. We postulate that MAIT cells are innate detectors of bacterial infection poised to play a role in control of intracellular infection.
Highlights
Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), remains a leading cause of infectious disease mortality worldwide [1]
We show that mucosal associated invariant T (MAIT) cells, which have no previously known in vivo function, make up a proportion of these Mtb-reactive CD8 T cells and detect Mtb-infected cells via a specific major histocompatibility molecule called MHC-related molecule 1, which is evolutionarily conserved among mammals
In individuals with no evidence of infection, we have consistently found high frequency CD8+ T cell responses against Mtb-infected dendritic cell (DC)
Summary
Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), remains a leading cause of infectious disease mortality worldwide [1]. The majority of TB cases are exclusively pulmonary, suggesting a need for mucosal immunity in the control of Mtb. Th1-type immunity, including strong CD4+ Th1 cell and CD8+ T-cell responses, mediates control of Mtb infection [2]. Though many functions of CD4+ Th1 cells and CD8+ T cells are redundant, CD8+ T cells contrast with CD4+ cells in their ability to recognize MHC class II-negative cells and preferentially recognize cells heavily infected with Mtb [3]. Mtb-specific CD8+ T cells are present at high frequencies in both Mtb-infected and uninfected individuals [4,5]. The presentation of peptide antigen bound to HLA-A, B, or C to CD8+ T cells is well characterized [4,6] and has been termed HLA-Ia or classical antigen presentation
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