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

Mathew R., M.P. Seiler, S.T. Scanlon, A.P. Mao, M.G. Constantinides, C. Bertozzi-Villa, J.D. Singer, and A. Bendelac. 2012. BTB-ZF factors recruit the E3 ligase cullin 3 to initiate lymphoid effector programs. Nature 491:618-21.

Seiler M.P., R. Mathew, M.K. Liszewski, C. Spooner, K. Barr, F. Meng, H. Singh, and A. Bendelac. 2012. Elevated and sustained expression of the transcription factors Egr1 and Egr2 controls NKT lineage differentiation in response to TCR signaling. Nat. Immunol. 13: 264-71.

Scanlon, S.T., S.Y. Thomas, C.M. Ferreira, L. Bai, T. Krausz, P.B. Savage, and A. Bendelac. 2011. Airborne lipid antigens mobilize resident intravascular NKT cells to induce allergic airway inflammation. J Exp Med 208:2113-24

Thomas, S.Y., S.T. Scanlon, K.G. Griewank, M.G. Constantinides, A.K. Savage, K.A. Barr, F. Meng, A.D. Luster, and A. Bendelac. 2011. PLZF induces an intravascular surveillance program mediated by long-lived LFA-1-ICAM-1 interactions. J Exp Med 208:1179-1188

Constantinides, M.G., D. Picard, A.K. Savage, A. Bendelac. 2011. A naive-like population of human CD1d-restricted T cells expressing intermediate levels of promyelocytic leukemia zinc finger. J Immunol 187, 309-315

Savage, A.K., M.G. Constantinides, and A. Bendelac. 2011. Promyelocytic leukemia zinc finger turns on the effector T cell program without requirement for agonist TCR signaling. J Immunol 186:5801-5806

Bai L., Y. Sagiv, Y. Liu, S. Freigang, K.O.A. Yu, L. Teyton, S.A. Porcelli, P.B. Savage, A. Bendelac. 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

Kreslavsky, T., A.K. Savage, R. Hobbs, F. Gounari, R. Bronson, P. Pereira, P.P. Pandolfi, A. Bendelac, and H. von Boehmer. 2009. TCR-inducible PLZF transcription factor required for innate phenotype of a subset of gammadelta T cells with restricted TCR diversity. Proc Natl Acad Sci U S A 106:12453-12458

Savage, A.K., M.G. Constantinides, J. Han, D. Picard, E. Martin, B. Li, O. Lantz, A. Bendelac. 2008. The transcription factor PLZF directs the effector program of the NKT cell lineage.  Immunity 29:391-403
Bendelac, A. 2008. NKT cells and other innatelike T and B lineages. Fundamental Immunology 6th Edition, W.E. Paul Editor, Lippincott Williams & Wilkins, pp518-46

Griewank K, C. Borowski, S. Rietdijk, N. Wang, 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, 751-762

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