NIH Training Grant Fellow: Milton Greenberg

Milton Greenberg

Milton's focus in the Cahalan lab in the Department of Physiology and Biophysics is centered on the development of new technologies as well as the application of tested methodologies to address fundamental immunological questions. His work spans the fields of biophysics, neuroscience and stem cell biology, but is centrally focused on advancing our knowledge of cellular immunology.

These efforts have resulted in publications and manuscripts that detail previously unrecognized mechanisms for immunological tolerance and cellular signaling. His work on B cell-induced tolerance has been published in the Proceedings of the National Academy of Sciences (PNAS) with a "must read" F1000 citation. Additionally, he recently received extremely positive reviewer comments from a recent submission to the Journal of Immunology, and he has two additional draft manuscripts to submit.

His research is focused on the development and application of new technologies to study the immune system. He has extensive experience in the development of new protocols, models and preparations for application in two-photon laser scanning microscopy. Utilizing immunocompromised mice, he is publishing the first study to ever examine human lymphocyte motility in the lymph node without reconstitution by fetal human tissue.

In addition, He has developed an ex vivo spinal cord imaging preparation, enabling the first description of neuronal progenitor cell migration in the central nervous system. Both of these technologies has the potential for broad applications in multiple scientific disciplines. In addition, he has worked to unveil mechanisms for cellular signaling and migration, and has several productive collaboration in diverse research areas.

Milton's experience at UCI has encouraged the development of collaborations throughout the campus. With the Lane lab, he is working to validate the use of neuronal progenitor cells as a treatment for the autoimmune disease multiple sclerosis. He has developed a tissue imaging protocol, making his the first group to visualize immune-mediated axonal damage in mouse hepatitis virus-induced EAE. Continuing development of imaging techniques has revealed the dynamic interactions that underlie stem cell-mediated repair of damaged axons. These discoveries are being molded into a potentially high-impact paper.

His work in visualizing dynamic lymphocyte interactions during the induction of peripheral tolerance changes how we understand the fundamental mechanism of CTLA-4 mediated immunosuppression. In previously published work, he has shown that LPS-activated "regulatory B cells" suppress the autoreactive T cell response by physically sequestering T cells in a dynamic, CTLA-4 dependent choreography. The revelation that CTLA-4 expressing lymphocytes can physically disrupt T cell priming has led to an important follow-up study examining how regulatory T cells modulate priming. As of now, this study will be the first to simultaneously visualize the interactions between autoreactive CD4+ T cells, regulatory T cellls and dendritic cells.

Through his participation in seminars, journal clubs and the immunology fair, he has gained an unparalleled, comprehensive understanding of the immune system. His recently submitted manuscript examining the role of CA2+ signaling in transendothelial migration was a massive effort, utilizing the expertise of many of his peers. He has been an active member in the immunology community, successfully establishing intracellular CA2+ imaging assays for the Casali, Lodoen and Hughes laboratories. Collaboration and insights from multiple investigators in this institute have provided him with proven results from demanding projects that have spanned the entire spectrum of immune research.

Publications:

Orai1 Function is Essential for T Cell Homing to Lymph Nodes
1. Greenberg, ML, Yu Y, Leverrier S, Zhang SL, Parker I, Cahalan, MD J Immunol. 2013 Mar 1.

Toll-like receptor 4-activated B cells out-compete Toll-like receptor 9-activated B cells to establish peripheral immunological tolerance
2. Matheu MP, Su Y, Greenberg ML, Blanc CA, Parker I, Scott DW, Cahalan MD. Proc Natl Acad Sci USA 2012 May 15; 109(20):E1258-66

Three Phases of CD8 T Cell Response in the Lung Following H1N1 Influenza Infection and Sphingosine 1 Phosphate Agonist Therapy
3. Matheu MP, Teijaro JR, Walsh KB, Greenberg ML, Marsolais D, Parker I, Rosen H, Oldstone MB, Cahalan MD