Immunology

Thierry Mallevaey PhD
Associate Professor
thierry mallevaey
Contact Info
T: (416) 978-7736
F: (416) 978-1938
Location
St. George Campus
University of Toronto, Medical Sciences Building
1 King's College Circle, Room 7308
Toronto, ON, M5S1A8
Accepting
Grad Students Must First Apply Through Department
Research Interests
Adaptive Immunity, Innate Immunity, iNK T-cells, Lipid immunity, Inflammation, Cancer, Microbiota

invariant Natural Killer T cells

The mammalian immune system contains unconventional T cells that recognize lipids presented by antigen-presenting molecules of the CD1 family. Lipid-reactive T cells are more prevalent and complex in humans than in mice, because humans express four CD1 isoforms (CD1a-d), whereas mice only express CD1d. Most of our understanding of lipid immunity mainly focuses on a subset of CD1d-restricted T cells called invariant Natural Killer T (iNKT) cells.

Our overarching objective is to understand how lipid-reactive T cells develop and function, in order to target them in immunotherapies.

iNKT cells exert innate-like functions, and are conserved among most mammals. Upon activation, iNKT cells produce copious amounts of cytokines and chemokines within only minutes, which influence many other innate and adaptive immune cells. Consistent with this, iNKT cells can suppress or enhance immune responses during cancer, autoimmunity, allergy and infection. The array of functions carried out by iNKT cells highlight their functional flexibility in vivo. Although the mechanisms underlying their functional plasticity are poorly understood, the perspective of manipulating iNKT cell responses holds great promise to treat various diseases.

Our main research projects currently focus on:

  1. The mechanisms by which iNKT cells develop and acquire their innate effector functions. We use genetically-modified mouse models, retrovirus-mediated gene deliver and/or silencing, as well as in vitro models of T cell development.
  2. How iNKT cells and the intestinal microbiota influence each other, and how these interactions impact on the development of intestinal inflammation. We use germ-free mice, fecal transplant approaches, colonization with candidate microbes and established animal models of colitis.
  3. The development of novel reagents to identify and track other lipid-reactive T cells. We use nanotechnologies in collaboration with biochemists and chemical engineers. We focus primarily on the elusive CD1d-restricted diverse Natural Killer T (dNKT) cells.
  4. Targeting iNKT cells in adoptive cell therapy to treat cancer. We engineer iNKT cells to give them the ability to recognize tumour-associated antigens, and assess their ability to kill melanoma and lymphoma cells in vitro and in vivo.

Publications and Awards

Recent Publications

 

  1. Invariant NKT Cell Activation Is Potentiated by Homotypic trans-Ly108 Interactions. Baglaenko Y, Cruz Tleugabulova M, Gracey E, Talaei N, Manion KP, Chang NH, Ferri DM, Mallevaey T, Wither JE. J Immunol. 2017 May 15;198(10):3949-3962.
  2. 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.
  3. 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.
  4. 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.
  5. Antagonizing Peroxisome Proliferator-Activated Receptor α Activity Selectively Enhances Th1 Immunity in Male Mice. Zhang MA, Ahn JJ, Zhao FL, Selvanantham T, Mallevaey T, Stock N, Correa L, Clark R, Spaner D, Dunn SE. J Immunol. 2015 Dec 1;195(11):5189-202.
  6. Effective functional maturation of invariant natural killer T cells is constrained by negative selection and T-cell antigen receptor affinity. Bedel R, Berry R, Mallevaey T, Matsuda JL, Zhang J, Godfrey DI, Rossjohn J, Kappler JW, Marrack P, Gapin L. Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):E119-28.
  7. 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.