The Immune Response to Lipids

Immune responses are initiated when T cells recognize antigens displayed by antigen presenting cells (APC). Classically, T cell recognition is towards peptide antigens displayed on APC by MHC molecules. More recently, lipid antigens were found to be similarly displayed by the MHC-like molecule, CD1, and recognized by an unconventional class of T cells, including NKT cells. We are interested in exploring the biology of lipid antigen recognition by T cells, and the role this has in a number of human diseases, including autoimmune diseases such as multiple sclerosis, diabetes and lupus, infectious diseases as well as inflammatory diseases such as atherosclerosis.

We have recently discovered a new role for the serum lipoprotein apoE in the immune response to lipid antigens. We will continue to explore the role of apolipoproteins in lipid antigen presentation as this has particular relevance to diseases such as atherosclerosis and autoimmune disease.

A major endeavor will be to identify lipid and glycolipid antigens that are presented by CD1 to T cells in various physiological settings and the role they play in disease. This will involve screening of candidate lipid antigens, as well as discovery approaches to find novel lipid antigens from various biological sources (cells, tissues or blood).


Generation of a multi-antigen-directed immune response for durable control of acute lymphoblastic leukemia
DOI: 10.1038/leu.2017.290

Activation of invariant natural killer T cells stimulated with microbial a-mannosyl glycolipids
Scientific Reports
Michio Shimamura and Masaki Yamamura and Tatsuya Nabeshima and Naoki Kitano and Peter van den Elzen and Hasan Yesilkaya and Peter Andrew and Petr Illarionov
DOI: 10.1038/s41598-017-10309-x

Autoreactivity to Sulfatide by Human Invariant NKT Cells
The Journal of Immunology
Annelein M. Stax and Jessica Tuengel and Enrico Girardi and Naoki Kitano and Lenka L. Allan and Victor Liu and Dongjun Zheng and William J. Panenka and Joren Guillaume and Chi-Huey Wong and Serge van Calenbergh and Dirk M. Zajonc and Peter van den Elzen
DOI: 10.4049/jimmunol.1601976

Innate immune control of EBV-infected B cells by invariant natural killer T cells
B. K. Chung and K. Tsai and L. L. Allan and D. J. Zheng and J. C. Nie and C. M. Biggs and M. R. Hasan and F. K. Kozak and P. van den Elzen and J. J. Priatel and R. Tan
DOI: 10.1182/blood-2013-01-480665

NKT Cells Are Required for Complete Freund's Adjuvant-Mediated Protection from Autoimmune Diabetes
The Journal of Immunology
I.-F. Lee and P. van den Elzen and R. Tan and J. J. Priatel
DOI: 10.4049/jimmunol.1002551

CD1d and CD1c Expression in Human B Cells Is Regulated by Activation and Retinoic Acid Receptor Signaling
The Journal of Immunology
L. L. Allan and A. M. Stax and D.-J. Zheng and B. K. Chung and F. K. Kozak and R. Tan and P. van den Elzen
DOI: 10.4049/jimmunol.1003615

Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity
Journal of Clinical Investigation
Ya-Jen Chang and Hye Young Kim and Lee A. Albacker and Hyun Hee Lee and Nicole Baumgarth and Shizuo Akira and Paul B. Savage and Shin Endo and Takashi Yamamura and Janneke Maaskant and Naoki Kitano and Abel Singh and Apoorva Bhatt and Gurdyal S. Besra and Peter van den Elzen and Ben Appelmelk and Richard W. Franck and Guangwu Chen and Rosemarie H. DeKruyff and Michio Shimamura and Petr Illarionov and Dale T. Umetsu
DOI: 10.1172/jci44845

Acidification-dependent Activation of CD1d-restricted Natural Killer T Cells is Intact in Cystic Fibrosis
Clinical Immunology
Aaron Hirschfeld and Sarah Rzemieniak and Rachel Victor and Mark Chilvers and Dongjun Zheng and Peter van den Elzen and Stuart Turvey
DOI: 10.1016/j.clim.2010.03.330

Apolipoprotein-mediated lipid antigen presentation in B cells provides a pathway for innate help by NKT cells
L. L. Allan and K. Hoefl and D.-J. Zheng and B. K. Chung and F. K. Kozak and R. Tan and P. van den Elzen
DOI: 10.1182/blood-2009-04-211417

Seven Surprises in the TCR-Centred Regulation of Immune Responsiveness in an Autoimmune System
Generation and Effector Functions of Regulatory Lymphocytes
Eli Sercarz and Emanual Maverakis and Peter van den Elzen and Loui Madakamutil and Vipin Kumar
DOI: 10.1002/0470871628.ch12

Administration of PLP139-151 Primes T Cells Distinct from Those Spontaneously Responsive In Vitro to This Antigen
The Journal of Immunology
R. Penitente and C. Nicolo and P. Van den Elzen and G. Di Sante and C. Agrati and F. Aloisi and E. E. Sercarz and F. Ria
DOI: 10.4049/jimmunol.180.10.6611

A public T cell clonotype within a heterogeneous autoreactive repertoire is dominant in driving EAE
Journal of Clinical Investigation
Juscilene S. Menezes and Peter van den Elzen and Jordan Thornes and Donald Huffman and Nathalie M. Droin and Emanual Maverakis and Eli E. Sercarz
DOI: 10.1172/jci28277

Conserved and Heterogeneous Lipid Antigen Specificities of CD1d-Restricted NKT Cell Receptors
The Journal of Immunology
M. Brigl and P. van den Elzen and X. Chen and J. H. Meyers and D. Wu and C.-H. Wong and F. Reddington and P. A. Illarianov and G. S. Besra and M. B. Brenner and J. E. Gumperz
DOI: 10.4049/jimmunol.176.6.3625

Apolipoprotein-mediated pathways of lipid antigen presentation
Peter van den Elzen and Salil Garg and Luis León and Manfred Brigl and Elizabeth A. Leadbetter and Jenny E. Gumperz and Chris C. Dascher and Tan-Yun Cheng and Frank M. Sacks and Petr A. Illarionov and Gurdyal S. Besra and Sally C. Kent and D. Branch Moody and Michael B. Brenner
DOI: 10.1038/nature04001

CD1 assembly and the formation of CD1–antigen complexes
Current Opinion in Immunology
David L Hava and Manfred Brigl and Peter van den Elzen and Dirk M Zajonc and Ian A Wilson and Michael B Brenner
DOI: 10.1016/j.coi.2004.12.003

Limited clonality in autoimmunity: drivers and regulators
Autoimmunity Reviews
Peter van den Elzen and Juscilene S. Menezes and Akio Ametani and Emanual Maverakis and Loui Madakamutil and Xiao-lei Tang and Vipin Kumar and Eli E. Sercarz
DOI: 10.1016/j.autrev.2004.07.008

Autoreactive T cells can be protected from tolerance induction through competition by flanking determinants for access to class II MHC
Proceedings of the National Academy of Sciences
E. Maverakis and J. Beech and D. B. Stevens and A. Ametani and L. Brossay and P. van den Elzen and R. Mendoza and Q. Thai and L. H. Macias and D. Ethell and C. W. Campagnoni and A. T. Campagnoni and A. Sette and E. E. Sercarz
DOI: 10.1073/pnas.0936151100

Differential Expression of T-bet, a T-box Transcription Factor Required for Th1 T-Cell Development, in Peripheral T-Cell Lymphomas
American Journal of Clinical Pathology
David M. Dorfman and MD and PhD and Peter van den Elzen and MD and Andrew P. Weng and MD PhD and Aliakbar Shahsafaei and MS and Laurie H. Glimcher and MD
DOI: 10.1309/j3ct-lttj-evuy-4yl0

Molecular Characterization of the T Cell Repertoire Using Immuno-scope Analysis and its Possible Implementation in Clinical Practice
Current Molecular Medicine
F. Ria and P. Elzen and L. Madakamutil and J. Miller and E. Maverakis and E. Sercarz
DOI: 10.2174/1566524013363690

Self-reactive T cells and Degeneracy of T Cell Recognition: Evolving Concepts—from Sequence Homology to Shape Mimicry and TCR Flexibility
Journal of Autoimmunity
Emanual Maverakis and Peter van den Elzen and Eli E Sercarz
DOI: 10.1006/jaut.2000.0493

Residual public repertoires to self
Journal of Neuroimmunology
Stephen S Wilson and Peter van den Elzen and Emanual Maverakis and Jonathan T Beech and Todd A Braciak and Vipin Kumar and Eli E Sercarz
DOI: 10.1016/s0165-5728(00)00218-6

Inhibition and acceleration of Na+/Ca2+/K+ exchange fluxes by Ag+ in bovine retinal rod outer segments
American Journal of Physiology-Cell Physiology
P. P. Schnetkamp and R. T. Szerencsei and J. E. Tucker and P. Van den Elzen
DOI: 10.1152/ajpcell.1995.269.5.c1147


Clinical Interests
Transfusion Medicine
Immune Monitoring
Flow Cytometry

The role of NKT cells in the immune response
An important subset of CD1 restricted T cells include “NKT” cells which recognize glycolipids presented by CD1d. NKT cells have been shown to play many diverse roles in immunity from the regulation of autoimmune diseases such as type 1 diabetes to a pro-inflammatory role in diseases such as atherosclerosis. We are studying the mechanisms by which NKT cells exert this control, from their effect on B cells in the production of antibodies, to their effect on classical T cell immunity mediated by CD4+ and CD8+ T cells.

Autoimmunity to lipid antigens: The role of CD1-restricted T cells and apolipoproteins
We are exploring whether autoimmunity to self lipids plays a role in the pathophysiology of diseases such as multiple sclerosis, diabetes, lupus and atherosclerosis. This involves characterization of lipid-reactive T cells and anti-lipid antibodies from the peripheral blood or tissues of patients and in animal models of disease.

In multiple sclerosis, the lipid-rich myelin sheath is a target of immune attack, and we are exploring whether this attack is directed at the lipid components of myelin and the role that lipid transport proteins such as apoE have in this recognition.

In type 1 diabetes, autoimmunity is directed against pancreatic beta cells and a regulatory role exists for NKT cells, which recognize glycolipid antigens. We are working to determine the mechanism of this regulation and the role that lipid/glycolipid recognition has in this process.

Lupus is also characterized by autoimmunity to self antigens, and this may include lipid antigens such as phospholipids and blood borne lipids found in lipoproteins.

Atherosclerosis is the underlying cause of the highest number of deaths in the Western World, and the inflammatory process that causes it likely begins early in life, and is particularly a byproduct of diseases such as diabetes, lupus and arthritis. Perturbations in blood lipids are a key feature of atherosclerosis, as is an inflammatory response in the walls of blood vessels. Our work, which defines a pathway by which the immune system directly targets blood lipids, has important implications for the pathogenesis of atherosclerosis. We are exploring whether serum lipids can be targeted in atherosclerosis and associated conditions.

The discovery of lipid antigens that are targeted by the immune system will lead to lipid-based therapies which can alter the immune response.

Honours & Awards

Michael Smith Foundation for Health Research 2007, Career Investigator Award 2007-2013

Multiple Sclerosis Society of Canada, Career Development Award 2007-2010

Research Group Members

Mairead Cavinaw, Directed Studies Student, Research Assistant
Nicholas Fisher, Graduate Student
Joshua Koentjoro, Undergraduate Student
Curtis Logan, Undergraduate Student
Rana Minab, Doctoral Student
Rebecca Siemes, Trainee
Dong Jun Zheng, Research Asst/Tech 4