Unconventional T cells to Fight Tuberculosis and Cancers
MAIT cell subset is becoming a promising T cell candidate to fight infections and cancers. Animal studies in mice at a loss-of-function of antigen-presentation and gain-of-expression of MAIT TCR supported a protective role of MR1 and MAIT cells in fighting Mycobacterium tuberculosis infections. However, its protection in larger animals and humans required to be further tested using optimal strategies for MAIT cell stimulation. We will apply animal models to understand MAIT cell activation and protection in M. tuberculosis infections.
Peptide-specific conventional T cells have been major targets for designing most antimycobacterial vaccines. Immune responses mediated by conventional T cells exhibit a delayed onset upon primary infection and are highly variable in different human populations. In contrast, innate-like T cells quickly respond to pathogens and display effector functions without undergoing extensive clonal expansion. Specifically, the activation of innate-like T cells depends on the promiscuous interaction of highly conserved antigen-presenting molecules, non-peptidic antigens, and likely semi-invariant T cell receptors. In antimicrobial immune responses, mucosal-associated invariant T cells are activated by riboflavin precursor metabolites presented by major histocompatibility complex-related protein I, while lipid-specific T cells including natural killer T cells are activated by lipid metabolites presented by CD1 proteins. Multiple innate-like T cell subsets have been shown to be protective or responsive in mycobacterial infections. Through rapid cytokine secretion, innate-like T cells function in early defense and memory response, offering novel advantages over conventional T cells in the design of anti-tuberculosis strategies.
Le Bourhis, Lionel, Emmanuel Martin, Isabelle Péguillet, Amélie Guihot, Nathalie Froux, Maxime Coré, Eva Lévy, et al. (2010) 2010. “Antimicrobial Activity of Mucosal-Associated Invariant T Cells”. Nature Immunology 11 (8): 701-8. https://doi.org/10.1038/ni.1890.
Mucosal-associated invariant T lymphocytes (MAIT lymphocytes) are characterized by two evolutionarily conserved features: an invariant T cell antigen receptor (TCR) alpha-chain and restriction by the major histocompatibility complex (MHC)-related protein MR1. Here we show that MAIT cells were activated by cells infected with various strains of bacteria and yeast, but not cells infected with virus, in both humans and mice. This activation required cognate interaction between the invariant TCR and MR1, which can present a bacteria-derived ligand. In humans, we observed considerably fewer MAIT cells in blood from patients with bacterial infections such as tuberculosis. In the mouse, MAIT cells protected against infection by Mycobacterium abscessus or Escherichia coli. Thus, MAIT cells are evolutionarily conserved innate-like lymphocytes that sense and help fight off microbial infection.
