Dissecting the role of CD1c-autoreactive T cells in mycobacterium tuberculosis infection

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of Tuberculosis (TB), remains the world’s leading infectious disease killer. The only available TB vaccine, BCG, provides limited protection against pulmonary TB in adults and adolescents and the emergence of drug-resistant strains are threatening global TB control. CD1c-restricted T cells are an intriguing target for boosting immunity of future TB vaccines, as the non-polymorphic CD1c antigen-presenting system can mediate immune responses to lipid antigens, such as those found in the lipid-rich Mtb cell wall. This feature offers a promising strategy to overcome inter-individual variability in immune responses and increase the efficacy of future TB vaccines. Although CD1c-restricted T cells are thought to contribute to host defence against Mtb, a substantial proportion are autoreactive, recognising self-lipids presented byCD1c. The functional significance of these CD1c-autoreactive responses during Mtb infection, however, remains unknown.

Adding complexity, Mtb has evolved immune evasion strategies that may directly target this lipid antigen presentation pathway. Previous studies suggest that Mtb infection downregulates the expression of group 1 CD1 molecules (CD1a, CD1b, and CD1c) on antigen-presenting cells (APCs), potentially impairing CD1-mediated T cell surveillance. To investigate this, we analysed RNA sequencing data from Mtb infected monocyte-derived dendritic cells (MoDCs), revealing a marked reduction in transcripts for all group 1 CD1 molecules. These findings were corroborated in vitro, where Mtb infection led to significant downregulation of surface CD1 expression on MoDCs. Despite these challenges, understanding the role of CD1c-autoreactive T cells in TB immunity remains a key goal. One major barrier to progress has been the difficulty in generating pure CD1c-autoreactiveT cell lines. To overcome this, we developed a robust in vitro platform for the enrichment and expansion of these cells. Using this system, we performed co-culture assays with Mtb infected CD1c+ APCs.

Remarkably, CD1c-autoreactive T cells showed enhanced activation, increased cytotoxicity, and elevated secretion of IL-1α and IL-1β in response to Mtb infected compared to uninfected APCs. Most notably, these T cells demonstrated direct antimicrobial activity, suppressing Mtb growth within infected APC cultures. Mechanistic studies using Jurkat cells transduced with CD1c-autoreactive T cell receptor (TCR)s confirmed that these responses were TCR- and CD1c-dependent, establishing a clear link between CD1c autoreactivity and Mtb recognition.

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Identifiers

ORCID for Matthew Milton: orcid.org/0000-0003-2509-7171

ORCID for Salah Mansour: orcid.org/0000-0002-5982-734X

ORCID for Paul Elkington: orcid.org/0000-0003-0390-0613

ORCID for Diana Garay Baquero: orcid.org/0000-0002-9450-8504

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