Identification and thymic development of human autoreactive iNKT cells — ASN Events
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  2. Poster Session 2 - Even Numbers + Rapid Fire 2 Posters
  3. Identification and thymic development of human autoreactive iNKT cells

Identification and thymic development of human autoreactive iNKT cells (#146)

Jeanne Perroteau 1 , Leslie HESNARD 1 , Marie-Claire DEVILDER 1 , Laurent GAPIN 2 , Emmanuel SCOTET 1 , Xavier SAULQUIN 1 , Laetitia GAUTREAU-ROLLAND 1
  1. Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA) - UMR Inserm 1232 - ERL CNRS 6001 - Université de Nantes, Nantes, FRANCE, France
  2. National Jewish Health and University of Colorado, Denver, Colorado, USA

Invariant Natural Killer T (iNKT) lymphocytes express both NK receptors and a semi-invariant αβ TCR (T Cell Receptor), which is restricted by the CD1d molecule presenting glycolipid antigens. Among them, αGalactosylCeramid (αGalCer) is a potent ligand of all iNKT cells. In some contexts, iNKT cells are also able to detect endogenous glycolipids, which suggests an autoreactive potential of some of them. However, the mechanisms that regulate this autoreactivity are poorly understood, especially in humans, because of the difficulty to detect and isolate autoreactive iNKT cells ex vivo.

We have previously studied the thymic maturation of human antigen-specific conventional T cells (Hesnard et al., 2016), using a highly sensitive tetramer-based immunomagnetic cell separation approach (Legoux et al., 2010). In this study, we extended this strategy to the analysis of human iNKT lymphocytes. αGalCer-CD1d tetramers were used to identify the total iNKT cell population, while ones loaded with the partial agonist α-linked glycolipid OCH detected putative autoreactive iNKT cells, as documented by the group of S. Gadola (Matulis et al., 2010). Phenotypic and frequency analyses of iNKT stained by αGalCer- and/or OCH-CD1d tetramers allowed us to decipher intrathymic selection mechanisms that occur during human iNKT cell development. Moreover, we generated iNKT cell lines from the peripheral blood of healthy donors and identified some human iNKT cell lines showing a strong autoreactive activity against target cells expressing endogenous glycolipids-CD1d complexes. The cloning of cells from these autoreactive lines evidenced various autoreactivity levels, that suggest a TCR variability, which is currently analyzed.

Altogether, our results indicate the existence of autoreactive subsets of human iNKT cells in the peripheral blood in healthy donors. Importantly, we show for the first time that these lymphocytes have probably circumvented thymic selection processes and can be involved in various physiopathological contexts such as autoimmune diseases or cancers.