AIRRC7 - Leveraging single-cell TCR-sequencing to investigate mucosal T cell biology (N. Provine)

"Leveraging single-cell TCR-sequencing to investigate mucosal-associated invariant T cell biology"
Nicholas Provine, University of Oxford, Group Leader

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are abundant in human blood and non-lymphoid tissues. MAIT cells recognize microbial metabolites through a semi-invariant T cell receptor (TCR) and can be activated in a TCR-independent manner by cytokines. Correlative and mechanistic studies have implicated a role for MAIT cells in an expanding array of infectious and inflammatory diseases. However, major questions remain regarding the extent of human MAIT cell functional and clonal diversity, particularly the minor interleukin (IL)-17-producing fraction. To address these questions, we analyzed the single-cell transcriptome and TCR repertoire of blood and liver MAIT cells and developed functional RNA-sequencing (fRNA-seq), a method to integrate function and TCR clonotype at single-cell resolution. Despite a semi-invariant TCR, MAIT cell clonal diversity was comparable to conventional memory T cells, with private TCR repertoires shared across matched tissues. Baseline functional diversity was low and largely related to tissue site. Transcriptional responses in vitro were stimulus-specific, with cells positioned along gradients of activation. Clonal origin influenced resting and activated transcriptional profiles, but intriguingly was not associated with the capacity to produce IL-17. Instead, clonal tracking suggested equal capacity of cells to make IL-17 under appropriate conditions. Overall, MAIT cells at rest exhibit diverse donor-specific TCR repertoires linked to their phenotype, and functional diversity according to both clonotype and stimulus. These data reinforce the utility of single-cell TCR-sequencing to contextualize phenotypic and functional analysis of T cell populations.

AIRR Community Meeting VII – Learnings and Perspectives
June 3-6, 2024
University of Porto, Porto, Portugal
https://www.antibodysociety.org/the-a...