Thierry Mallevaey

iNKT and MAIT cells

The mammalian immune system contains unconventional T cells that recognize lipids and small molecule metabolites, two antigenic reservoirs that are invisible to conventional T cells. Lipid-reactive T cells are more prevalent and complex in humans than in mice. Most of our understanding of lipid immunity is on the so-called invariant Natural Killer T (iNKT) cells. However, other populations of lipid-reactive T cells do exist in mammals. Mucosa-associated invariant T (MAIT) cells constitute another population of unconventional T cells specialized in the recognition of microbial vitamin derivatives. iNKT and MAIT cells exert potent functions in tumour immunity as well as autoimmune, allergic and inflammatory diseases such as type 1 diabetes and Crohn’s disease. Our overarching objective is to understand how unconventional T cells develop and function, in order to target them in immunotherapies.

iNKT and MAIT cells are a population of evolutionarily conserved T cells that have been identified in mammals that possess both innate and adaptive characteristics. They are capable of rapidly secreting cytokines, chemokines, and cytotoxic molecules within minutes to hours upon stimulation. Unlike conventional T cells, which respond to peptide antigens presented by major histocompatibility complex (MHC) molecules, iNKT cells recognize lipid antigens – such as a-galactosylceramide (aGC) – presented by the MHC Class I-like molecule CD1d, and MAIT cells respond to riboflavin (vitamin B2) metabolites presented by the MHC Class I-like molecule MR1. Both iNKT cells can be further divided into discrete effector subsets that are reminiscent of conventional T cells or innate lymphoid cells (ILCs). Consistent with this, iNKT and MAIT cells can suppress or enhance immune responses during cancer, autoimmunity, allergy, and infection. The array of functions carried out by these T cells highlight their functional flexibility in vivo. Although the mechanisms underlying their functional plasticity are poorly understood, the perspective of manipulating iNKT and MAIT cell responses holds great promise to treat various diseases.

Our main research projects currently focus on:

1. The mechanisms by which iNKT and MAIT cells develop and acquire their innate effector functions. We use genetically modified mouse models, retrovirus-mediated gene delivery and/or silencing, as well as in vitro models of T cell development.
2. How iNKT/MAIT cells and the intestinal microbiota influence each other, and how these interactions impact on the development of inflammation or anti-tumour responses. We use germ-free mice, dirty mice, fecal transplant approaches, colonization with candidate microbes, and established animal models of liver and intestinal inflammation.

Selected publications:

1. Dirty mice join the immunologist’s toolkit. Kuypers M, Despot T, Mallevaey T. Microb Infec. 2021 Jul; 23(6-7):104817. doi: 10.1016/j.micinf.2021.104817.
2. Altered Innate-like T Cell Development in Vα14-Jα18 TCRα Transgenic Mice. Lau I, de Amat Herbozo C, Kuypers M, Lin Q, Paget C, Mallevaey T. Immunohorizons. 2020 Dec; 4(12):797-808.
3. The dialogue between unconventional T cells and the microbiota. Lin Q, Kuypers M, Philpott DJ, Mallevaey T. Mucosal Immunol. 2020 Nov; 13(6):867-876.
4. High Dimensional Single-Cell Analysis Reveals iNKT Cell Developmental Trajectories and Effector Fate Decision. Baranek T, Lebrigand K, de Amat Herbozo C, Gonzalez L, Bogard G, Dietrich C, Magnone V, Boisseau C, Jouan Y, Trottein F, Si-Tahar M, Leite-de-Moraes M, Mallevaey T, Paget C. Cell Rep. 2020 Sep; 32(10):108116. doi:10.1016/j.celrep.2020.108116.
5. The Protein Phosphatase Shp1 Regulates Invariant NKT Cell Effector Differentiation Independently of TCR and Slam Signaling. Cruz Tleugabulova M, Zhao M, Lau I, Kuypers M, Wirianto C, Umaña JM, Lin Q, Kronenberg M, Mallevaey T. J Immunol. 2019 Apr 15;202(8):2276-2286.
6. SLAM receptors foster iNKT cell development by reducing TCR signal strength after positive selection. Lu Y, Zhong MC, Qian J, Calderon V, Cruz Tleugabulova M, Mallevaey T, Veillette A. Nat Immunol. 2019 Apr;20(4):447-457.
7. Synthesis of Patient-Specific Nanomaterials. Lazarovits J, Chen YY, Song F, Ngo W, Tavares AJ, Zhang YN, Audet J, Tang B, Lin Q, Tleugabulova MC, Wilhelm S, Krieger JR, Mallevaey T, Chan WCW. Nano Lett. 2019 Jan 9;19(1):116-123.
8. The common mouse protozoa Tritrichomonas muris alters mucosal T cell homeostasis and colitis susceptibility. Escalante NK, Lemire P, Cruz Tleugabulova M, Prescott D, Mortha A, Streutker CJ, Girardin SE, Philpott DJ, Mallevaey T. J Exp Med. 2016 Dec 12;213(13):2841-2850.
9. NKT Cell-Deficient Mice Harbor an Altered Microbiota That Fuels Intestinal Inflammation during Chemically Induced Colitis. Selvanantham T, Lin Q, Guo CX, Surendra A, Fieve S, Escalante NK, Guttman DS, Streutker CJ, Robertson SJ, Philpott DJ, Mallevaey T. J Immunol. 2016 Dec 1;197(11):4464-4472.
10. Discrete TCR Binding Kinetics Control Invariant NKT Cell Selection and Central Priming. Cruz Tleugabulova M, Escalante NK, Deng S, Fieve S, Ereño-Orbea J, Savage PB, Julien JP, Mallevaey T. J Immunol. 2016 Nov 15;197(10):3959-3969.
11. Nod1 and Nod2 enhance TLR-mediated invariant NKT cell activation during bacterial infection. Selvanantham T, Escalante NK, Cruz Tleugabulova M, Fiévé S, Girardin SE, Philpott DJ, Mallevaey T. J Immunol. 2013 Dec 1;191(11):5646-54.