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