Flash Talk & Poster CD1-MR1 2024

Innate-like T cell subset commitment in the murine thymus is independent of TCR characteristics and occurs during proliferation (#126) (#61)

Vadim Karnaukhov 1 2 , Anne-Laure Le Gac 1 , Linda Bilonda Mutala 1 , Aurélie Darbois 1 , Laetitia Perrin 1 , Francois Legoux 1 3 , Aleksandra Walczak 2 , Thierry Mora 2 , Olivier Lantz 1 4 5
  1. Institut Curie, Paris, PARIS, France
  2. Laboratoire de physique, École normale supérieure, PSL Université, Paris, France
  3. Institut de Génétique & Développement de Rennes, Université de Rennes, Rennes, France
  4. Laboratoire d'immunologie clinique, Institut Curie, Paris, France
  5. Centre d'investigation Clinique en Biothérapie Gustave-Roussy Institut Curie, Paris, France

T-cell receptor (TCR) binding to its ligand(s) is essential for T-cell development into several distinct lineages. The strength of this interaction and physico-chemical characteristics of TCR were previously shown to govern commitment to particular fates (e.g. T cells with hydrophobic TCRs preferentially acquire regulatory phenotype). It is not clear if this conclusion applies to other T cell subsets, in particular, to innate-like T cells: mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells. MAIT and iNKT cells have similar developmental paths, leading in mice to two effector subsets, cytotoxic (MAIT1/iNKT1) and IL17-secreting (MAIT17/iNKT17). For iNKT1 vs iNKT17 fate choice, an instructive role for TCR affinity was proposed but recent data argue against this model. In the current study, we examined TCR role in MAIT and iNKT subset commitment through scRNA-seq and scTCR-seq analysis. First, in our dataset of thymic MAIT cells, we found pairs of T-cell clones with identical amino acid TCR sequences but originating from distinct precursors, one of which committed to MAIT1 and the other to MAIT17 fates. Quantitative in silico simulations indicated that the number of such cases is most likely explained by lineage choice being independent of TCR characteristics. Comparison of TCR features of MAIT1 and MAIT17 clonotypes demonstrated that the subsets cannot be distinguished based on TCR sequence. To pinpoint the developmental stage associated with MAIT sublineage choice, we demonstrated that proliferation takes place both before and after MAIT fate commitment. Altogether, we propose a model of MAIT cell development in which non-committed, intermediate-stage MAIT cells undergo a first round of proliferation, followed by TCR characteristics-independent commitment to MAIT1 or MAIT17 lineage, followed by an additional round of proliferation. By reanalyzing a published iNKT TCR dataset, we showed that this model is also relevant for iNKT cell development.