- Professor, Department of Pathology, Cancer Research Center, Committee on Immunology
M.D., University of Paris VI, Paris, 1985
Ph.D., University of Paris VI, Paris, 1992
The University of Chicago
929 East 57th Street
Chicago, Illinois 60637
Phone: (773) 834-8646
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.