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Appointments:
<>Professor
Department of Pathology
Investigator, Howard Hughes
Medical Institute
Cancer Research Center
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Education:
M.D., University of Paris VI, Paris,
1995
Ph.D., University of Paris VI, Paris, 1992
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Contact:
Phone: (773) 834-8646
Fax: (773)
834-1999
E-Mail:
abendela@bsd.uchicago.edu
Address:
The University of Chicago
GCIS W506
929 East 57th Street
Chicago, Illinois 60637
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Related Research Interests:
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Albert Bendelac, M.D., Ph.D.
Interfaces Between Innate and Adaptive Immunity; Immune
Recognition of Glycolipids; CD1-mediated Glycolipid Antigen Presentation
Research Summary
CD1-mediated Antigen Presentation; Development and
Functions of Glycolipid-Specific T cells
T cell Responses Leading to Type I Diabetes in Mice and Humans
CD1-mediated Antigen Presentation - Development and
Functions of Glycolipid-Specific T cells
CD1-mediated Antigen Presentation. In parallel with the MHC antigen
presentation pathway, which presents protein antigens to T lymphocytes,
the CD1 pathway evolved to present lipid antigens. Because, microbes
can rapidly mutate their proteins but not their lipids to evade immune
recognition, these complementary strategies respond to different
evolutionary pressures. Our laboratory is exploring the biochemistry
and cell biology of glycolipid antigen processing and presentation by
CD1 molecules and the development, diversity and functions of
glycolipid-specific T cells, We have mapped several steps of the
intra-cellular pathway of CD1 trafficking and uncovered critical genes
involved in antigen processing and presentation in the endosomal
compartment. Most exciting is our recent discovery, in close
interdisciplinary collaboration with colleagues at Scripps Research
Institute and Brigham Young University, that saposins and other lipid
transfer proteins play crucial functions in assisting lipid exchange
between membrane compartments and CD1.
We
have also discovered that, in contrast with MHC-specific T cells, many
T cells with CD1-specific T cell receptors follow a developmental
pathway leading to a hybrid NK/T lineage. By developing fluorescent CD1
tetramers to label these cells, we were able to physically track their
developmental pathway at the single cell level and explore the cellular
interactions and signaling pathways involved. We are creating various
transgenic models in vivo in mice and in vitro in organ culture
systems, to further dissect the mechanisms underlying the development
and the function of glycolipid-specific T cells.
By
enhancing our understanding of the mechanisms underlying glycolipid
recognition by T cells, these studies might lead to various clinical
applications. The conservation of CD1 genes across species and the
limited ability of microbes to alter their lipids through gene mutation
suggest that 'universal' glycolipid-based vaccines and adjuvants might
be developed in the near future. In addition, CD1 regulates the immune
rejection of cancer and appear to prevent type I diabetes, providing
exciting avenues for basic as well as clinically applied research.
Type I Diabetes
Type I diabetes is a disease of world-wide importance, affecting 1% of
the American population during their lifetime, particularly in
childhood. The disease is caused by T cells that are aberrantly
directed against self-antigens expressed by insulin-producing cells in
the pancreas, a breakdown of tolerance to self. We are studying the
non-obese diabetic (NOD) mouse strain, which spontaneously expresses
type I diabetes by 12-24 weeks of age. We found that disease could be
transferred upon injection of T cells from diabetic mice into younger
healthy recipients, and that full blown diabetes required both CD4 and
CD8 T cells. We are focusing on two aspects of the disease process that
might be amenable to immune intervention in order to prevent disease.
Firstly, we are studying the diabetogenic CD8 T cells, the only
cell-type that can directly interact with the insulin-producing cells,
likely therefore to be the key downstream agent of this complex
autoimmune process. Secondly, we are studying the role of
CD1-restricted NKT cells, whose recruitment appears to protect against
disease. These approaches might lead to novel strategies aiming at
predicting and preventing disease in genetically predisposed
individuals.
Selected Papers
Bendelac A, Carnaud C, Boitard C, Bach JF. (1987).
Syngeneic
transfer of autoimmune
diabetes from diabetic NOD mice to healthy neonates. Requirement for
both L3T4+ and Lyt2+ T cells. J. Exp. Med. 166 : 823-832.
Bendelac A, Boitard C, Bedossa P, Bazin H, Bach JF,
Carnaud C. (1988). Adoptive T cell
transfer of autoimmune nonobese diabetic mouse diabetes does not
require recruitment of host B lymphocytes. J Immunol. 1988 Oct
15;141(8):2625-8.
Benlagha K, Weiss A, Beavis A, Teyton L, Bendelac A.
(2000). In vivo
identification of glycolipid antigen specific T cells using fluorescent
CD1d tetramers. J. Exp. Med. 191:1895-1903.
Jayawardena-Wolf J, Benlagha K, Chiu YH, Mehr R,
Bendelac A. (2001). CD1d endosomal
trafficking is independently regulated by an intrinsic CD1d-encoded
tyrosine motif and by the invariant chain. Immunity 15, 897-908.
Chiu YH, Park SH, Benlagha K, Forestier C,
Jayawardena-Wolf J, Savage PB, Teyton L, Bendelac A. (2002). Multiple
defects in antigen presentation
and T cell development by mice expressing cytoplasmic tail-truncated
CD1d. Nature Immunology 3, 55-60.
Bendelac A, Medzhitov R. (2002). Adjuvants of Immunity:
Harnessing Innate Immunity
To Promote Adaptive Immunity. J. Exp. Med., 195, 19-23
Benlagha K, Kyin T, Beavis A, Teyton L, Bendelac A.
(2002). A thymic precursor to the NKT cell lineage. Science 296,
553-555.
Honey K, Benlagha K, Beers C, Forbush K, Teyton L,
Rudensky AY, Bendelac A.
(2002). Thymocyte expression of cathepsin L is critical for NK T cell
development. Nature Immunol, 3, 1069-1074.
Lee PT, Putnam A, Benlagha K, Teyton L, Gottlieb PA,
Bendelac A. (2002). Testing
the NKT cell hypothesis of human IDDM pathogenesis. J Clin Invest.
Sep;110(6):793-800.
Forestier C, Park SH, Wei D, Benlagha K, Teyton L,
Bendelac A.
(2003). T cell development in mice expressing CD1d directed by a
classical MHC class II promoter. J Immunol. 171, 4096-4104.
Cantu C III, Benlagha K, Savage PB, Bendelac A, Teyton
L. (2003). The
paradox of immune molecular recognition of a-galactosylceramide: low
affinity, low specificity for CD1d, high affinity for ab T cell
receptors J. Immunol. 170, 4673-4682.
Benlagha K, Park SH, Guinamard R, Forestier C, Karlsson
L, Chang CH, Bendelac A. (2004). Mechanisms governing B cell
developmental
defects in invariant chain-deficient mice. J Immunol. 172, 2076-2083.
Zhou D, Cantu C III, Sagiv Y, Schrantz N, Kulkarni AB,
Qi X, Mahuran DJ, Morales CR, Grabowski GA, Benlagha K, Savage P,
Bendelac A, TeytonL. (2004). Editing of CD1d-bound lipid antigens by
endosomal lipid transfer proteins. Science. 303, 523-527.
Goff RD, Gao Y, Mattner J, Zhou D, Yin N, Cantu C III,
Teyton L, Bendelac A, Savage PB. (2004). Effects of lipid chain lengths
in
a-galactosylceramides on cytokine release by natural killer T cells. J.
Am. Chem. Soc., 126:13602-13603.
Zhou D, Mattner J, Cantu C III, Schrantz N, Yin N, Gao
Y, Sagiv Y, Hudspeth K, Wu Y, Yamashita T, Teneberg S, Wang D,
Proia R, Levery SB, Savage PB, Teyton L, Bendelac A. (2004). Lysosomal
glycosphingolipid recognition by NKT cells. Science, 306:1786-9.
Benlagha K, Wei DG, Veiga J, Teyton L, Bendelac A.
(2005).
Characterization of the early
stages of thymic NKT cell development. J. Exp. Med. 202, 485-92.
Zajonc DM, Cantu C III, Mattner J, Zhou D, Savage PB,
Bendelac A, Wilson IA, Teyton L. (2005). Structure and function of a
potent
agonist for the semi-invariant NKT cell receptor. Nature Immunol. 6,
810-8.
Wei DG, Lee H, Park S-H, Beaudoin L, Teyton L, Lehuen A,
Bendelac A. (2005). Expansion and long range
differentiation of the NKT cell lineage in mice expressing CD1d
exclusively on cortical thymocytes. J. Exp. Med. 202, 239-48.
Egawa T, Eberl G, Taniuchi I, Benlagha K, Geissmann F,
Hennighausen L, Bendelac A, Littman DR. (2005). Genetic
evidence supporting selection of the Vα14i NKT
cell lineage from
double positive thymocyte precursors. Immunity 22, 705-716.
Borowski C, Bendelac A. (2005). Signaling for NKT cell
development: the SAP-Fyn connection. J. Exp. Med. 201, 833-6.
Mattner J, DeBord KL, Ismail N, Goff RD, Cantu C
III, Zhou D, Saint-Mezard P, Wang V, Gao Y, Yin N, Hoebe K, Schneewind
O, Walker D, Beutler B, Teyton L, Savage PB*, Bendelac A*. (2005). Both
exogenous and endogenous glycolipid antigens
activate NKT cells during microbial infections. Nature 434, 525-9
*co-senior authors.
Benlagha K, Wei DG, Veiga J, Teyton L, Bendelac A.
(2005). Characterization of the early stages of thymic NKT cell
development. J. Exp. Med. 202, 485-92
Zajonc DM, Cantu C III, Mattner J, Zhou D, Savage PB,
Bendelac A, Wilson IA, Teyton L. (2005). Structure and function of a
potent agonist for the semi-invariant NKT cell receptor. Nature
Immunol. 6, 810-8
Wei DG, Curran SA, Savage PB, Teyton L,
Bendelac A. (2006).
Mechanisms imposing the Vß bias of Vα 14 natural
killer T cells and
consequences for microbial glycolipid recognition. J. Exp.
Med.
203, 1197-1207
Liu Y, Goff RD, Zhou D, Mattner J, Sullivan BA,
Khurana A, Cantu C III, Ravkov EV, Ibegbu CC, Altman JD, Teyton L,
Bendelac A, Savage PB. (2006). A modified alpha-galactosyl ceramide for
staining and stimulating natural killer T cells. J Immunol Methods.
312, 34-39
Sagiv Y, Hudspeth K, Mattner J, Schrantz N, Stern RK,
Zhou D, Savage PB, Teyton L, Bendelac A. (2006). Cutting edge:
impaired
glycosphingolipid trafficking and NKT cell development in mice lacking
niemann-pick type c1 protein. J Immunol. 177, 26-30
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