Human CD1c-autoreactive T-cells recognise Mycobacterium tuberculosis-infected antigen-presenting cells and display cytotoxic effector programmes.

Authors

Matthew Milton, Sahar H Farag, Diana Garay-Baquero, Jennie Gullick, Kinga Niedobecka, Daniel Burns, Rita Szoke-Kovacs, Patrick Trimby-Smith, Alex Look, Richard Stopforth, Marco Lepore, David K Cole, Laura Denney, Andrew White, Sally Sharpe, Alasdair Leslie, Andres Vallejo, Liku Tezera, Paul Elkington, Salah Mansour

Published in

eLife. Volume 15. Oct 05, 2026. Epub Oct 05, 2026.

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death from infection globally yet the contribution of non-classical T-cell pathways to human immunity remains poorly defined. CD1c-autoreactive T-cells, which recognise self-lipids presented by the antigen-presenting molecule CD1c, are frequent in human blood but their role during infection remains unclear. Here, we investigate how CD1c-expressing antigen-presenting cells (APCs) and Mtb infection shape CD1c-autoreactive T-cell responses using engineered human APC systems, complemented by single-cell transcriptomic profiling to define the ex vivo phenotypic landscape of these T-cells. CD1c is present within human TB granulomas, whereas Mtb down-modulates CD1c expression on infected APCs, consistent with an immune evasion strategy. CD1c-autoreactive T-cells respond more strongly to Mtb-infected CD1c⁺ APCs than to uninfected cells, exhibiting enhanced activation, cytotoxicity, and diverse cytokine secretion via CD1c-dependent recognition. Under in vitro conditions, these T-cells reduce relative Mtb burden in infected phagocytes. Single-cell RNA sequencing reveals cytotoxic effector-memory programmes and expression of antimicrobial molecules, providing a mechanistic basis for these responses. Together, these findings define a human CD1c-restricted T-cell response to Mtb-infected APCs and identify autoreactive CD1c-restricted T-cells as a candidate cellular axis for lipid-directed immunity in TB.

PMID:
42832565
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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