A.N. Pritzker Professor, Committee on Immunology
Department of Pathology
The University of Chicago
Gordon Center for Integrative Science (GCIS)
929 East 57th Street, Room W-506
Chicago, IL 60637
773.702.9199 (Jill Voss, Administrative Assistant)
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. In that respect, they closely resemble innate lymphocytes such as NK cells and other Innate Lymphoid Cells (ILC). These innate and innate-like lymphoid populations 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 focused on NKT cells, a prominent population of innate-like 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.
Our recent studies of NKT cell development have identified the signature transcription factor Promyelocytic Leukemia Zinc Finger (PLZF) encoded by Zbtb16, which is necessary and sufficient for acquisition of the effector program in the thymus. We generated PLZF-reporter mice and showed that PLZF expression was a canonical feature of most innate lymphocytes, at least during development. For example, ILC were fate-mapped by a PLZF-Cre allele, although the mature ILC did not express PLZF anymore. We exploited this property to identify and characterize the elusive committed precursor to ILC based on PLZF expression in fetal liver and in bone marrow. Furthermore, by crossing PLZF-Cre mice to ROSA26-DTa mice carrying a conditional diphtheria toxin gene, we have generated mice selectively lacking innate lymphocytes, but with normal adaptive B and T cells. Thus, basic studies of transcription and development have led to the generation of powerful new tools to assess the function of innate lymphocytes in vivo.
Constantinides, M.G., McDonald, B.D., Verhoef, P.A., and A. Bendelac. 2014. A committed precursor to innate lymphoid cells. Nature doi 10.1038/nature13047 (in press).
Bai, L., S. Deng, R. Reboulet, R. Mathew, L. Teyton, P.B. Savage, and A. Bendelac. 2013. Natural killer T (NKT)-B-cell interactions promote prolonged antibody responses and long-term memory to pneumococcal capsular polysaccharides. Proc. Natl Acad. Sci (USA) 110:16097-16102.
Luoma, A.M., C.D. Castro, T. Mayassi, L.A. Bembinster, L. Bai, D. Picard, B. Anderson, L. Scharf, J.E. Kung, L.V. Sibener, P.B. Savage, B. Jabri, A. Bendelac, and E.J. Adams. 2013. Crystal Structure of Vdelta1 T Cell Receptor in Complex with CD1d-Sulfatide Shows MHC-like Recognition of a Self-Lipid by Human gammadelta T Cells. Immunity 39:1032-1042.
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