Howson, L. J. | bioRxiv Science

bioRxiv2025

Functional immune profiling reveals CD4+ T cell dysregulation associated with celiac disease

T cells integrate signals from antigen and co-stimulatory receptors to calibrate the strength and quality of their responses. This signal integration is influenced by genetic background, which can modulate thresholds for immune tolerance and strength of responses to threat. Celiac disease (CeD) is an autoimmune disorder driven by well-defined genetic risk and characterised by immune dysregulation in response to dietary gluten. However, whether sensitivity or response differences in naive T cell programming contributes to disease susceptibility is not known. To investigate such variation, we developed a sensitive quantitative platform, the momentum assay, which combines standardised, T cell activation with subsequent stimulus withdrawal, enabling measurement of T cell proliferation and survival over time. This assay is integrated with the Cyton2 mathematical model to infer underlying cellular timer programs from population-level dynamics. We applied this method to assess whether naive T cells from individuals with celiac disease (CeD) exhibited altered responses compared to healthy donors (HDs). We found that CD4+ but not CD8+ T cells from CeD patients showed a hypo-proliferative response following stimulation, associated with impaired secretion of the proliferative and pro-survival cytokine IL-2. Moreover, surface expression of early activation marker, CD69 remained elevated for longer on CD4+ T cells from CeD donors after stimulus withdrawal, suggesting prolonged activation and subtle alterations in regulatory feedback mechanisms. These findings reveal previously unrecognised quantitative alterations in naive T cell programming in CeD and underscore the utility of model-based analytical frameworks for detecting subtle functional perturbations in complex immune-mediated diseases.

immunology↗

bioRxiv2017

Diverse Streptococcus pneumoniae strains drive a MAIT cell response through MR1-dependent and cytokine-driven pathways

Mucosal Associated Invariant T (MAIT) cells represent an innate T cell population of emerging significance. These abundant cells can recognize ligands generated by microbes utilizing the riboflavin synthesis pathway, presented via the major histocompatibility complex (MHC) class I-related molecule MR1 and binding of specific T cell receptors (TCR). They also possess an innate functional programme allowing microbial sensing in a cytokine-dependent, TCR-independent manner. Streptococcus pneumoniae is a major human pathogen that is also associated with commensal carriage, thus host control at the mucosal interface is critical. The recognition of S. pneumoniae strains by MAIT cells has not been defined, nor have the genomics and transcriptomics of the riboflavin operon (Rib genes). We examined the expression of Rib genes in S. pneumoniae at rest and in response to metabolic stress and linked this to MAIT cell activation in vitro. We observed robust recognition of S. pneumoniae strains at rest and following stress, using both TCR-dependent and TCR-independent pathways. The pathway used was highly dependent on the antigen-presenting cell, but was maintained across a wide range of clinically-relevant strains. The riboflavin operon was highly conserved across a range of 571 S. pneumoniae from 39 countries dating back to 1916, and different versions of the riboflavin operon were also identified in related Streptococcus species. These data indicate an important functional relationship between MAIT cells and S. pneumoniae,which may be tuned by local factors, including the metabolic state of the organism and the antigen-presenting cell that it encounters.\n\nAuthor SummaryStreptococcus pneumoniae is the leading cause of bacterial pneumonia, causes invasive diseases such as meningitis and bacteraemia, and is associated with significant morbidity and mortality, particularly in children and the elderly. Here, we demonstrate that a novel T cell population called Mucosal-associated invariant T (MAIT) cells is able to respond to a diverse range of S. pneumoniae strains. We found that this response was dependent on the T cell receptor (which recognises metabolites of the bacterial riboflavin biosynthesis pathway), cytokines, and the type of antigen-presenting cell. A population genomics approach was also used to assess the prevalence and diversity of the genes encoding the riboflavin biosynthesis pathway among a large and diverse collection of S. pneumoniae. These genes were highly conserved across a range of 571 S. pneumoniae from 39 countries dating back to 1916, and was also present in other related Streptococcus species. Given the low levels of MAIT cells in neonates and MAIT cell decline in the elderly, both of whom are at the highest risk of invasive pneumococcal disease, further understanding of the functional role of MAIT cells in host defense against this major pathogen may allow novel therapeutics or vaccines to be designed.

immunology↗