Targeting Innate-Like T Cells in Tuberculosis

Abstract

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.

The generation of T‐cell memory to protect against tuberculosis

“…The recent demonstration of the protective effects of BCG revaccination against M. tuberculosis infection in adolescents and the M72/ASO1 E protein/adjuvant against pulmonary TB in adults with latent TB infection provides opportunities to define the parameters that correlate with protection against TB and instruct the development of improved vaccines. Such analysis would need to include the multitude of other immune parameters associated with M. tuberculosis infection, including tissue resident and/or stem cell memory T cells, Th17 cells, B cells or unconventional T cells . The exact contribution of this spectrum of immune responses to protective immunity in humans and their role as correlates of protection are to be resolved, highlighting the complexity of vaccine development against pathogens highly evolved to combat immune detection and clearance.…”

“…Such analysis would need to include the multitude of other immune parameters associated with M. tuberculosis infection, including tissue resident and/or stem cell memory T cells, Th17 cells, B cells or unconventional T cells. 57 The exact contribution of this spectrum of immune responses to protective immunity in humans and their role as correlates of protection are to be resolved, highlighting the complexity of vaccine development against pathogens highly evolved to combat immune detection and clearance.…”

“…Humans CD1‐restricted T cells recognizing M. tuberculosis cell wall products have been identified, while mucosa‐associated invariant T cells have been shown to detect intracellular infection with M. tuberculosis . Donor unrestricted T cells can produce effector cytokines, display cytolytic activity and are thought to represent an early line of defence against M. tuberculosis . Therefore, targeting unconventional T‐cell responses in humans may represent a feasible strategy for the early control of mycobacterial infection, particularly with the use of live vaccines; indeed, mucosa‐associated invariant T cells recognize macrophages infected with BCG and it would be of particular interest to determine whether other live vaccines in human trials (e.g.…”

“…56 Donor unrestricted T cells can produce effector cytokines, display cytolytic activity and are thought to represent an early line of defence against M. tuberculosis. 57 Therefore, targeting unconventional T-cell responses in humans may represent a feasible strategy for the early control of mycobacterial infection, particularly with the use of live vaccines; indeed, mucosa-associated invariant T cells recognize macrophages infected with BCG 58 and it would be of particular interest to determine whether other live vaccines in human trials (e.g. VPM1002 and MTBVAC, see Table 1) activate Donor unrestricted T cells.…”

Tuberculosis vaccines — perspectives from the NIH/NIAID Mycobacteria vaccine testing program

“…However, the study of non-traditional immune cells for the control of M. tuberculosis infection may also provide important new insight. Outside the question of “trained immunity”, interest has been directed at understanding the mechanism of innate lymphoid cells (ILC) such as mucosal associated invariant T (MAIT) cells, [37, 42, 49–52] invariant natural killer T (iNKT) cells [49, 53, 54] and NK T cells [55]. Whether these cells perform a direct effector function during infection is unclear, but they may be an early requirement for induction of protective immunity.…”