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DEPARTMENT OF IMMUNOLOGY & MICROBIOLOGY, A Leader in Immunology, Microbiology and Microbial Pathogenesis Research and Training

Immunology and Microbiology
 

Rachel S. Friedman, Ph.D.

Assistant Professor, Department of Biomedical Research at National Jewish Health


1400 Jackson St., K501b
Denver, CO 80206
Phone: 303-270-2558
E-mail: FriedmanR@njhealth.org

We are interested in understanding how T cell interactions with antigen presenting cells at the disease site can result in either T cell activation or tolerance. Our goals are to understand how the immune system dynamically regulates immune responses through cellular interactions and environmental cues, with the objective of developing therapeutic interventions to disrupt pathogenic cellular interactions that promote autoimmunity. 

Type 1 diabetes is an autoimmune disease in which the immune system attacks the insulin-producing beta cells of the pancreatic islets of Langerhans. Autoreactive islet-specific T cells are one of the primary mediators of beta cell destruction. We are working in moue models of type 1 diabetes to understand the cues at the disease site that promote T cell pathogenesis. More specifically, we are interested in elucidating how cellular interactions between T cells and APCs in the islets modulate T cell pathogenesis in type 1 diabetes. To do so we have developed a novel imaging methods to analyze live pancreatic islets via 2-photon microscopy that allows us to analyze immune cell motility and interactions within the islets, trafficking, and islet infiltration during type 1 diabetes (see video). 




Determining the outcome of the cellular interactions we analyze is an important next step in gleaning functional data from 2-photon microscopy. To that end, we have also developed methods to image biosensors that can dynamically read out cellular signaling or effector function acquisition in vivo. This allows us to directly analyze signaling events and modulation of cytokine production that occur during cellular interactions within their native tissue environment. Importantly, this will enable us to study the events and functional outcomes in the pancreatic islets that lead to pathogenic T cell activation or protective tolerance in real-time with the long term goal of therapeutically blocking the events or cellular interactions that induce T cell pathogenesis. 


We are also interested in understanding the mechanisms of T cell extravasation into the pancreatic islets. Using a novel method for intra-vital imaging of the pancreas, we have been able to directly observe and analyze the process of transendothelial migration (TEM) into the islets for the first time (see video). We have found that this process is much slower and more restrictive than TEM into the lymph nodes. Our goals are to identify determinants of TEM into the pancreatic islets and preferentially them to prevent TEM into the islets without preventing normal T cell trafficking throughout the body. In collaboration with the Jacobelli lab, we are testing whether targeting cytoskeletal effectors of actin polymerization will accomplish that goal.




















 


Rachel Friedman
Assistant Professor

FriedmanR@NJHealth.org

Robin Lindsay
Graduate Student, Immunology Program

Robin.Lindsay@UCDenver.edu

Adam Sandor
Graduate Student, Immunology Program

Adam.Sandor@UCDenver.edu

Matt Gerbert
Lab Researcher

GerbertM@NJHealth.org


​Robert Long
Lab Researcher

LongR@NJHealth.org

​Dayna Tracy
Lab Researcher

TracyD@NJHealth.org

​Seth Yannacone
Undergraduate Lab Assistant

syannaco@msudenver.edu

​Amber Zius
Post-baccalaureate Lab Assistant

azius@msudenver.edu
 
Dr. Rachel Friedman runs a joint lab with Dr. Jordan Jacobelli.
  • Friedman RS, Jacobelli J, Krummel MF.  Surface-bound chemokines capture and prime T cells for synapse formation.  Nature Immunology.  7:1101-1108. 2006.
  • Sabatos CA, Doh J, Chakravarti S, Friedman RS, Pandurangi PG, Tooley AJ, Krummel MF.  A Synaptic Basis for Paracrine Interleukin-2 Signaling during Homotypic T Cell Interaction.  Immunity.  29:238-248. 2008.
  • Gardner JM, Devoss JJ, Friedman RS, Wong DJ, Tan YX, Zhou X, Johannes KP, Su MA, Chang HY, Krummel MF, Anderson MS.  Deletional tolerance mediated by extrathymic Aire-expressing cells.  Science.  321:843-847. 2008.
  • Friedman RS*, Melli K*, Finger EB, Miao G, Szot GL, Krummel MF, Tang Q.  Amplification of autoimmune response through induction of dendritic cell maturation in inflamed tissues.  Journal of Immunology.  182: 2590-2600. 2009.  (*authors contributed equally)
  • Katzman SD, O'Gorman WE, Villarino AV, Gallo E, Friedman RS, Krummel MF, Nolan GP, Abbas AK.  Duration of antigen receptor signaling determines T-cell tolerance or activation.  PNAS.  107:18085-90. 2010.
  • Jacobelli J, Friedman RS, Conti MA, Lennon-Dumenil A-M, Piel M, Sorensen CM, Adelstein RS, Krummel MF. Myosin-IIA regulates lymphocyte adhesion and contractility during 3-dimensional amoeboid motility into and within lymph nodes.  Nature Immunology.  11:953-61. 2010.
  • Friedman RS, Beemiller P, Sorensen CM, Jacobelli J, Krummel MF.  Real-time analysis of TCRs in naïve cells in vitro and in vivo defines flexibility in synapse and signaling dynamics.  Journal of Experimental Medicine.  207:2733-49. 2010.
  • McKee AS, Burchill MA, Munks MW, Jin L, Kappler JW, Friedman RS, Jacobelli J, Marrack P.  Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells.  PNAS.  110:E1122-31. 2013.
  • Jacobelli J, Lindsay RS, Friedman RS.  Peripheral tolerance and autoimmunity: Lessons from in vivo imaging. Immunologic Research. 55:146-54. 2013.
  • Gérard A, Beemiller P, Friedman RS, Jacobelli J, Krummel MF.  Evolving immune circuits are generated by flexible, motile, and sequential immunological synapses. Immunological Reviews. 251:80-96. 2013.
  • Krummel MF, Friedman RS, Jacobelli J. Modes and mechanisms of T cell motility: roles for confinement and Myosin-IIA. Current Opinion in Cell Biology. 30: 9-16. 2014.
  • Friedman RS, Lindsay RS, Lilly JK, Nguyen V, Sorensen CM, Jacobelli J, Krummel MF.  An evolving autoimmune microenvironment regulates the quality of effector T cell restimulation and function.  PNAS.  111:9223-8. 2014.
  • Lindsay RS, Corbin K, Mahne A, Levitt BE, Gebert MJ, Wigton EJ, Bradley BJ, Haskins K, Jacobelli J, Tang Q, Krummel MF, Friedman RS. Antigen recognition in the islets changes with progression of autoimmune islet infiltration. Journal of Immunology.  194:522-30. 2015.