Research Advances

Faculty in the division continue to generate new insights into cellular and molecular mechanisms underlying protective and pathogenic immune responses. The Jordan lab has demonstrated that patients with a mutation in the LRBA gene which result in an autoimmune syndrome, can be successfully treated with Abatacept, a CTLA4-Ig fusion protein. In collaboration with the Lenardo lab (NIH), they revealed that LRBA controls the intracellular trafficking and surface expression of CTLA4 thereby providing a mechanistic basis for the efficacy of CTLA4-Ig. This is a powerful demonstration of moving research from the bedside to the bench, thereby enabling clinical investigations to reveal fundamental cell biological mechanisms operative in the immune system. The Grimes lab has generated a new mouse model of AML which is rapidly-lethal, completely-penetrant, transplantable and importantly displays a normal karyotype. It is based on Flt3-internal-tandem duplication (Flt3ITD) and inducible deletion of Dnmt3a. This is a powerful translational model for karyotypically normal human AML involving mutations in Flt3 and Dnmt3a genes. The Grimes and Singh labs are exploiting single cell transcriptional profiling to analyze normal hematopoiesis. This has led to the discovery of unusual mixed-lineage intermediates in myelopoiesis. The Singh lab has uncovered a regulatory module involving cross antagonism between the transcription factors IRF4 and IRF8 that controls affinity maturation of B cells and plasma cell differentiation. This work could enable the discovery of new biomarkers and drug targets for enhancing vaccine responses. The Chougnet lab is attempting to understand the effect of prematurity and inflammation, on the developing immune system. They have established that in utero exposure to IL-1 mediated inflammation affects the balance between fetal regulatory and effector T cells. Such dysregulation could explain the increased pulmonary morbidity in infancy that follows exposure to chorioamnionitis. While exploring T cell homeostasis, the Hildeman lab has shown that aged mice accumulate thymically derived regulatory T cells (Treg) having effector phenotype. IL-6 and ICOS signaling promote the accrual of effector Tregs, defining a novel feedback mechanism whereby inflammatory stimuli provoke a cellular anti-inflammatory response. Work in the Lewkowich lab is examining how the cytokine IL-17 functions in conjunction with IL-13 to induce more severe allergic asthma. Notably they have shown that IL-17 enhances IL-13-induced gene expression in asthma-relevant murine models and human epithelial cells via a mechanism involving more robust activation of Stat6. These findings represent the first mechanistic explanation of how IL-17 may directly contribute to the pathogenesis of IL-13-driven allergic asthma. The Herr lab in collaboration with the Farndale lab (University of Cambridge) has solved the crystal structures of the immune receptor OSCAR (osteoclast-associated receptor) alone and bound to its target, a collagen triple helix. This is the first structural data illustrating how an immune receptor in this family recognizes a collagenous ligand, and it has important implications for therapeutic intervention in osteoclast-associated disease states such as osteoporosis and rheumatoid arthritis.

Inter-Disciplinary Collaborations

Dr. Claire Chougnet, PhD, successfully spearheaded an inter-disciplinary collaborative proposal focused on perinatal infection and inflammation selected by the Academic Research Committee (ARC) for support. It involves a collaboration with colleagues in other divisions including Drs. Suhas Kallapur, Alan Jobe and Sing Sing Way.

Faculty Recruitment

Drs. Harinder Singh and David Hildeman conducted and led faculty searches in systems immunology and transplantation immunology, respectively. This led to the identification of two faculty candidates in systems immunology for recruitment, Wendy Huang (NYU) and Emily Miraldi (NYU). Dr. Virginia Miraldi will be joining the Division of Immunobiology as a faculty member in January 2017.

Systems Immunology Workshop

A workshop focused on systems immunology was co-organized by Drs. Singh and Herr. Accomplished postdoctoral fellows, from leading labs, made up the majority of invited speakers.. These next-generation scientists shared advances they are making in the analysis of gene regulatory and signaling networks; tracking of human immune responses using tools drawn from systems biology, and engineering of immune cells and immune receptors. The workshop elicited considerable interest from biotech and pharma companies, and was partially funded by AbbVie and Lycera. The workshop was a tremendous success and generated considerable institutional excitement for this emerging field that will greatly impact Immunology.

SAC Review

The division underwent a highly successful external review of its research and training programs. The research advances made by the faculty, along with the newly established inter-disciplinary collaborations, as well as the recruitment of faculty in systems immunology, were laudable. The two graduate training programs, Immunology (Cincinnati Children's and University of Cincinnati) and International Research Training Program (IRTG) (University of Lubeck) are regarded as excellent, with the latter noted for spawning international research collaborations.