Le mardi 3 décembre 2024, Chloé WILKIN présentera l'examen en vue de l’obtention du grade académique de Docteur en Sciences (Collège de doctorat en Biochimie, biologie moléculaire et cellulaire, bioinformatique et modélisation) sous la direction de Sylvie LEGRAND.

Cette épreuve consistera en la défense publique d’une dissertation intitulée :

“ Impact of obesity and dysglycemia on peripheral blood invariant Natural Killer T cells ”

Abstract

In addition to induce low-grade inflammation contributing to type 2 diabetes, obesity also causes immune dysregulation by negatively impacting several immune cell populations. This results in a loss of immunosurveillance which has been proposed to contribute to increased susceptibility of obese patients to suffer from more complications of infection and to develop some cancers.

Based on these considerations and because the frequency of peripheral invariant Natural Killer T (iNKT) cells is downmodulated in obesity, we hypothesized that an excessive activation of iNKT cells could result from the presentation of more or uncommon self-lipid antigen(s) via CD1d on antigen presenting cells (APCs) of patients with obesity. This chronic activation of peripheral iNKT cells could lead to their exhaustion and contribute to the loss of immunosurveillance. As dysglycemic obese (OBDysG) patients show a profound alteration of their phospholipidome in comparison to Leans but also normoglycemic obese (OBNG), we hypothesize that dysglycemia could worsen impact of obesity on iNKT cells.

A total of 54 individuals (aged between 18-65 years) were recruited on a voluntary basis. The participants were categorized in two groups based on the BMI: (i) Lean (BMI<25kg/m²; n=20) and (ii) Obese (BMI>30kg/m²; n=34). Obese group was further divided into two subgroups according to their glycemic profile (OBNG vs. OBDysG). Blood was sampled to characterize peripheral iNKT cells (phenotype and activity) and comparison was made between (1) Lean vs. Obese and OBNG vs. OBDysG individuals.

We have highlighted a disruption of peripheral iNKT cells in patients with obesity compared to lean individuals: 1) The absolute count of pro-inflammatory CD4- iNKT cells was reduced; 2) iNKT cells show an activated profile; 3) iNKT cells produce significantly less pro-inflammatory cytokines in response to ex vivo PMA-Ionomycin stimulation. Moreover, this strong alteration of iNKT cells seems to be correlated to plasma lipid content but not with glycemic status. Interestingly, nine months after bariatric surgery and significant weight loss, the iNKT cells' activated profile is reversed and their cytokine response is partially restored.

As iNKT cells mediate various immune responses in peripheral organs, such impact of obesity on iNKT cells function could participate to impaired immunosurveillance against microbial infections and tumors. 

Le Jury sera composé de :

Mme C. SADZOT (Présidente), Mmes et MM. T. ARNOULD (UNamur), N. ESSER (CHU), N. JACOBS (Secrétaire), S. LEGRAND (Promotrice), C. PAGET (Université de Tours), N. PAQUOT (CHU).