Albert Bendelac, M.D., Ph.D.

Innate Lymphocytes

Research Summary

The hallmark of adaptive immunity is the production of naïve B and T lymphocytes that traffic to lymph nodes and undergo clonal expansion upon exposure to antigen, followed by the acquisition of specialized effector functions and tissue migration properties. In contrast with this well-established scenario, many unconventional subsets of B and T cells undergo clonal expansion and acquire distinct effector differentiation and tissue homing properties during development, following exposure to endogenous rather than foreign ligands. These innate lymphocytes collectively represent a substantial fraction of total lymphocytes and are viewed as distinct lineages carrying out ‘hard-wired’ innate rather than adaptive strategies of immune defense. An understanding of their development and their role in health and disease has just begun to emerge. 

We focus on NKT cells, oneof the most prominent population of innate lymphocytes in mouse and human. NKT cells recognize key inflammatory and microbial lipids to trigger a cellular network that activates innate immunity, promotes adaptive immune responses and influences their T helper phenotype. Our studies seek an understanding of the cellular and molecular determinants of NKT lineage development, of their lipid antigens and the CD1 family of lipid-presenting molecules, and of their role in multiple diseases including allergic inflammation, infection, autoimmunity and cancer. We are also investigating synthetic NKT ligands as a new class of adjuvants for B cell vaccines, particularly against polysaccharide antigens, and CTL vaccines, for example against cancer. 

Selected Papers

D. Zhou, C. Cantu III, Y. Sagiv, N. Schrantz, A.B. Kulkarni, X. Qi, D.J. Mahuran, C.R.Morales, G.A. Grabowski, K. Benlagha, P.B. Savage, A. Bendelac, L. Teyton. 2004. Editing of CD1-bound lipid antigens by endosomal lipid transfer proteins. Science 303, 523-7

D. Zhou, J. Mattner, C. Cantu III, N. Schrantz, N. Yin, Y. Gao, Y. Sagiv, K. Hudspeth, Y. Wu, T. Yamashita, S. Teneberg, D. Wang,  R. Proia, S.B. Levery,  P.B. Savage,  Luc Teyton,  A. Bendelac. 2004. Lysosomal glycosphingolipid recognition by NKT cells. Science 306, 1786-9

J. Mattner, K.L. DeBord, N. Ismail, R.D. Goff, C. Cantu III, D. Zhou, P. Saint-Mezard, V. Wang, Y. Gao, N. Yin, K. Hoebe, O. Schneewind, D. Walker, B. Beutler, L. Teyton, P.B. Savage, A. Bendelac. 2005. Both exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434, 525-9 

C. Borowski, A. Bendelac. 2005. Signaling for NKT cell development: the SAP-Fyn connection. J. Exp. Med.  201, 833-6

D.G. Wei, H. Lee, S.-H. Park, L. Beaudoin, L. Teyton, A. Lehuen, A. Bendelac. Expansion and long range differentiation of the NKT cell lineage in mice expressing CD1d exclusively on cortical thymocytes. 2005. J. Exp. Med. 202, 239-48

D.M. Zajonc, C. Cantu III, J. Mattner, D. Zhou, P.B. Savage, A. Bendelac, I.A. Wilson, L. Teyton. 2005. Structure and function of a potent agonist for the semi-invariant NKT cell receptor. Nature Immunol. 6, 810-8

K. Benlagha, D.G. Wei, J. Veiga, L. Teyton, A. Bendelac. 2005. Characterization of the early stages of thymic NKT cell development. J. Exp. Med. 202, 485-92

D.G. Wei, S.A. Curran, P.B. Savage, L. Teyton, A. Bendelac. 2006. Mechanisms imposing the Vb bias of Va14 NKT cells and consequences for microbial glycolipid recognition. J. Exp. Med. 203, 1197-1207.

Y. Sagiv, K. Hudspeth, J. Mattner, N. Schrantz, R.K. Stern, D. Zhou, P.B. Savage, L. Teyton, A. Bendelac. 2006. Impaired glycosphingolipid trafficking and NKT cell development in mice lacking Niemann-Pick type C1 (NPC1) protein.  J. Immunol [Cutting Edge] 177, 26-30.

X Long, Deng S, Mattner J, Zang Z, Zhou D, McNary N, Goff RD, Teyton L, Bendelac A, Savage PB. 2007. Synthesis and evaluation of stimulatory properties of Sphingomonadaceae glycolipids. Nat Chem Biol. 3:559-64

K. Griewank, C. Borowski, S. Rietdijk, A. Julien, D.G. Wei, A.A. Mamchak, C. Terhorst, A. Bendelac. 2007. Homotypic interactions mediated by Slamf1 and Slamf6 control NKT lineage development.  Immunity.  27:751-62

A. Bendelac, P.B. Savage, L. Teyton. 2007. The biology of NKT cells Annu Rev Immunol. 25, 297-336

Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, Scanlon ST, Pendem K, Teyton L, Hart J, Ridgway WM, Wicker LS, Gershwin ME, Bendelac A. Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe. 2008 May 15;3(5):304-15.

Zajonc DM, Savage PB, Bendelac A, Wilson IA, Teyton L. Crystal structures of mouse CD1d-iGb3 complex and its cognate Valpha14 T cell receptor suggest a model for dual recognition of foreign and self glycolipids. J Mol Biol. 2008 Apr 4;377(4):1104-16.

Savage AK, Constantinides MG, Han J, Picard D, Martin E, Li B, Lantz O, Bendelac A. 2008. The Transcription Factor PLZF Directs the Effector Program of the NKT Cell Lineage. Immunity. 29:391-403.

Dose M, Sleckman B, Han J, Bredemeyer A, Bendelac A, Gounari F. 2009. Intrathymic proliferation wave essential for Va14+ natural killer T cell development depends on c-Myc. Proc. Natl Acad. Sci (USA) 106:8641-6

Bai L, Sagiv Y, Liu Y, Freigang S, Yu KOA, Teyton L, Porcelli SA, Savage PB, Bendelac A. 2009. Lysosomal recycling terminates CD1d-mediated presentation of short and polyunsaturated variants of the NKT cell lipid antigen aGalCer. Proc. Natl Acad. Sci (USA) 106, 10254-9