A.N. Pritzker Professor, Committee on Immunology
Department of Pathology and the College
The University of Chicago
Donnelley Biological Sciences Learning Center (BSLC)
Jules F. Knapp Medical Research Center (JFK)
924 E. 57th St., Room R-210
Chicago, IL 60637
773.834.4878 (Divya Gala, Administrative Specialist)
Innate and Innate-Like Lymphocytes in Immunity and Homeostasis
Unlike conventional T and B cells of adaptive immunity, innate-like B and T cell lineages acquire effector differentiation and tissue residency properties during development, following exposure to endogenous rather than foreign ligands. In that respect, they closely resemble Innate Lymphoid Cells (ILC) and together they represent a substantial fraction of total lymphocytes in tissues and at mucosal barriers, carrying out first-line defense and promoting recruitment of subsequent adaptive immunity. Studies in our laboratory aim at understanding their identity, development, and role in health and disease.
Our early studies focused on NKT cells, a prominent population of innate-like T lymphocytes in mouse and human that are characterized by the expression of semi-invariant TCRs with specificity for microbial and self lipids presented by the CD1 family of MHC1 like molecules. These studies led to the identification of the signature transcription factor Promyelocytic Leukemia Zinc Finger (PLZF) encoded by Zbtb16, which is necessary and sufficient for acquisition of the NKT cell effector program in the thymus. By generating PLZF-reporter mice, we discovered that PLZF expression during development was a signature feature not only for NKT cells, but also for most innate and innate-like lymphocyte lineages. For example, a high level of PLZF expression identified the common precursor to ILC. Furthermore, by performing PLZF ChIP-seq analysis, we identified the targets of PLZF and defined the genetic architecture of the innate lymphoid effector program.
Most recently, we have initiated studies of other lineages of innate-like lymphocytes. By cloning and transgenically expressing TCRs of innate-like intestinal intraepithelial lymphocytes, we have characterized their unusual specificity and developmental pathway in vivo. Likewise, by cloning and transgenically expressing B cell receptors of intestinal lamina propria B cells, we are defining the development and specificity of IgA secreting B cells and their role in microbiota homeostasis.
Collectively, our studies define the identity, the development, and the functional contribution of the myriad lineages that populate tissues and mucosal barriers in the steady state. They generate knowledge of critical molecular components, for example, transcription factors, that define these lineages and allow the generation of reporter mice where these lineages can be easily identified and manipulated in vivo to explore their roles in homeostasis and in various disease conditions.
Bunker, J.J., Erickson, S.A., Flynn, T.M., Henry, C., Koval, J.C., Meisel, M., Jabri, B., Antonopoulos, D.A., Wilson, P.C., and Bendelac, A. (2017). Natural polyreactive IgA antibodies coat the intestinal microbiota. Science 358.
Ishizuka, I.E., Chea, S., Gudjonson, H., Constantinides, M.G., Dinner, A.R., Bendelac, A., and Golub, R. (2016a). Single-cell analysis defines the divergence between the innate lymphoid cell lineage and lymphoid tissue-inducer cell lineage. Nat Immunol 17, 269-276.
Ishizuka, I.E., Constantinides, M.G., Gudjonson, H., and Bendelac, A. (2016b). The Innate Lymphoid Cell Precursor. Annu Rev Immunol 34, 299-316.
Mao, A.P., Constantinides, M.G., Mathew, R., Zuo, Z., Chen, X., Weirauch, M.T., and Bendelac, A. (2016). Multiple layers of transcriptional regulation by PLZF in NKT-cell development. Proc Natl Acad Sci U S A 113, 7602-7607.
Verhoef, P.A., Constantinides, M.G., McDonald, B.D., Urban, J.F., Jr., Sperling, A.I., and Bendelac, A. (2016). Intrinsic functional defects of type 2 innate lymphoid cells impair innate allergic inflammation in promyelocytic leukemia zinc finger (PLZF)-deficient mice. J Allergy Clin Immunol 137, 591-600 e591.
Bunker, J.J., Flynn, T.M., Koval, J.C., Shaw, D.G., Meisel, M., McDonald, B.D., Ishizuka, I.E., Dent, A.L., Wilson, P.C., Jabri, B., Antonopoulos, D.A., and Bendelac, A. (2015). Innate and Adaptive Humoral Responses Coat Distinct Commensal Bacteria with Immunoglobulin A. Immunity 43, 541-553.
Constantinides, M.G., Gudjonson, H., McDonald, B.D., Ishizuka, I.E., Verhoef, P.A., Dinner, A.R., and Bendelac, A. (2015). PLZF expression maps the early stages of ILC1 lineage development. Proc Natl Acad Sci U S A 112, 5123-5128.
Constantinides, M.G., McDonald, B.D., Verhoef, P.A., and Bendelac, A. (2014). A committed precursor to innate lymphoid cells. Nature 508, 397-401.
Mathew, R., Mao, A.P., Chiang, A.H., Bertozzi-Villa, C., Bunker, J.J., Scanlon, S.T., McDonald, B.D., Constantinides, M.G., Hollister, K., Singer, J.D., Dent, A.L., Dinner, A.R., and Bendelac, A. (2014). A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation. J Exp Med 211, 1137-1151.
McDonald, B.D., Constantinides, M.G., and Bendelac, A. (2013). Polarized effector programs for innate-like thymocytes. Nat Immunol 14, 1110-1111.
Constantinides, M.G., and Bendelac, A. (2013). Transcriptional regulation of the NKT cell lineage. Curr Opin Immunol 25, 161-167.
Mathew, R., Seiler, M.P., Scanlon, S.T., Mao, A.P., Constantinides, M.G., Bertozzi-Villa, C., Singer, J.D., and Bendelac, A. (2012). BTB-ZF factors recruit the E3 ligase cullin 3 to regulate lymphoid effector programs. Nature 491, 618-621.
Thomas, S.Y., Scanlon, S.T., Griewank, K.G., Constantinides, M.G., Savage, A.K., Barr, K.A., Meng, F., Luster, A.D., and Bendelac, A. (2011). PLZF induces an intravascular surveillance program mediated by long-lived LFA-1-ICAM-1 interactions. J Exp Med 208, 1179-1188.