Human CD1c-autoreactive T-cells recognise <i>Mycobacterium tuberculosis</i>-infected antigen-presenting cells and display cytotoxic effector programmes

Tuberculosis, a leading cause of death from infection worldwide, is primarily caused by Mycobacterium tuberculosis. Despite extensive research, the role of non-classical T-cell pathways in human immunity remains unclear. CD1c-autoreactive T-cells, which recognize self-lipids presented by the antigen-presenting molecule CD1c, are common in human blood, but their role during infection is still unknown.

To better understand the function of CD1c-autoreactive T-cells during infection, researchers investigated how these T-cells interact with antigen-presenting cells (APCs) infected with Mtb. Using engineered human APC systems and single-cell transcriptomic profiling, the team examined the ex vivo phenotypic landscape of these T-cells.

The study found that CD1c is present within human TB granulomas and that Mtb down-regulates CD1c expression on infected APCs, suggesting an immune evasion strategy employed by the pathogen. CD1c-autoreactive T-cells responded more strongly to Mtb-infected CD1c+ APCs than to uninfected cells, displaying enhanced activation, cytotoxicity, and diverse cytokine secretion. This enhanced response was attributed to the CD1c-dependent recognition of infected APCs.

In vitro experiments showed that these T-cells can reduce the relative Mtb burden in infected phagocytes. Single-cell RNA sequencing revealed cytotoxic effector-memory programs and the expression of antimicrobial molecules in CD1c-autoreactive T-cells, providing a mechanistic basis for their enhanced response. The findings suggest that CD1c-restricted T-cells play a significant role in the body's lipid-directed immunity against TB.