A conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant trehalose monomycolate

Area of Science:

• Immunology
• Microbiology
• Structural Biology

Background:

• Mycobacterium tuberculosis possesses a lipid cell wall, prompting human immune responses against its lipids, often acting as adjuvants via innate immune receptors.
• While some mycobacterial lipids are known antigens for T cells, the antigenicity of most adjuvant lipids remains uncharacterized.

Purpose of the Study:

• To identify the antigenicity of trehalose monomycolate (TMM), an abundant mycobacterial adjuvant.
• To investigate the mechanism of T cell activation by TMM and its recognition by the immune system.

Main Methods:

• Utilized CD1b-TMM tetramers for single-cell TCR-RNA-Seq to identify TMM-specific T cells.
• Employed cryo-electron microscopy to study the structural complex of CD1b-TMM-TCR.
• Analyzed T cell responses including cytokine production (IFN-γ, TNF) and effector functions.

Main Results:

• Identified TMM as an activator of human T cells expressing a specific αβ T cell receptor (αβTCR), restricted by CD1b.
• Discovered TMM-specific CD4+ effector memory T cells in uninfected individuals, which produce anti-mycobacterial effectors upon stimulation.
• Observed expansion of these T cells in active tuberculosis patients and their presence in cord blood.

Conclusions:

• Humans possess a shared, pre-formed CD4+ T cell subset that recognizes the mycobacterial adjuvant TMM as an antigen.
• The dual role of TMM as both an adjuvant and a T cell antigen necessitates a re-evaluation of how immune adjuvants function.