Research Program: Immunology
Assistant Professor, Department of Laboratory Medicine and Pathology

farra005@umn.edu
612-625-0401 — office
612-625-3608 — lab
Preferred contact method: Email

Dr. Farrar received his Ph.D. in Immunology in 1993 from Washington University in St. Louis. He conducted postdoctoral training in the laboratory of Dr. Roger Perlmutter in the Department of Immunology at the University of Washington and later at Merck Research Labs in Rahway, NJ. He joined the University of Minnesota Cancer center in 2000, where he conducts research on signal transduction pathways that regulate lymphocyte development.

Research Interests

Signal transduction and lymphocyte development Research in my lab explores how signal transduction pathways regulate lymphocyte development and activation. Lymphocytes develop from hematopoietic stem cells and go through characteristic stages of differentiation that results in the formation of functional, mature T or B cells. These stages are carefully regulated by the action of growth factor and cytokine receptors, as well as the clonotypic T cell and B cell antigen receptors. A key question is how signaling pathways downstream of these receptors regulate various aspects of B and T cell maturation. Current efforts in the lab seek to elucidate how two such pathways, the Ras and Jak/STAT signaling cascades, entrain these developmental processes. This is being done using a variety of techniques, including retroviral expression strategies and the use of mice expressing dominant negative and activated Ras, Raf and STAT transgenes, in concert with subtractive cDNA libraries and gene microarray technology. Using these approaches we have recently discovered that activation of the transcription factor STAT5 is sufficient to rescue B cell, but not T cell, development in interleukin-7-receptor deficient mice. In addition, we also have evidence that the STAT5 pathway may play an important role in the process that regulates whether a hematopoeitic stem cell will develop into a B or T cell (lineage commitment). To more precisely identify STAT5 gene targets involved in these processes, we have developed a novel, chemical-induced dimerization approach that allows us to selectively activate the STAT5 signaling pathway in the absence of confounding signals from other signal transduction pathways. Using this approach, we hope to identify novel STAT5 targets, in both developing B and T cells, that regulate lymphocyte development and lineage commitment.

The other major question we seek to address is how distinct signaling pathways govern lymphocyte activation. For example, we have recently discovered a role for STAT5 signaling in the development of regulatory T cells (Tregs). Tregs are required to prevent autoimmunity; mice and humans which lack Tregs develop multiple autoimmune syndromes. We have demonstrated that mice which lack STAT5 also fail to develop Tregs. Conversely, constitutive activation of STAT5 in Tregs leads to a large increase in this cell type. We are currently studying the molecular mechanisms by which STAT5 alters Treg development and function. In addition, we seek to determine whether Tregs with enhanced STAT5 signaling act as more efficient suppressors of autoimmune disorders such as diabetes, systemic lupus erythematosis, or inflammatory bowel disease.

Selected Publications

Farrar MA, Alberola-Ila J, Perlmutter RM. Direct activation of the Raf-l kinase cascade via coumermycin-induced dimerization. Nature 1996;383:178-181.

Iritani BM, Forbush KA, Farrar MA, Perlmutter RM. Control of B Cell Development by Ras-mediated Activation of Raf. EMBO J. 1997;16:7019-7031.

Burchill MA, Goetz CA, Prlic M, O'Neil JJ, Harmon IR, Bensinger SJ, Turka LA, Brennan P, Jameson SC, Farrar MA. Distinct effects of STAT5 activation on CD4+ and CD8+ T cell homeostasis: Development of CD4+CD25+ regulatory T cells versus CD8+ memory T cells. J. Immunol. 2003;171:5853-5864.

Goetz CA, O'Neil JJ, Farrar MA. Membrane localization, oligomerization, and phosphorylation are required for optimal Raf activation. J Biol Chem. 2003;19;278:51184-51189.

Goetz CA, Harmon IR, O'Neil JJ, Burchill MA, Farrar MA. STAT5 activation underlies interleukin-7-dependent B cell but not T cell development. J Immunol. 2004;172:4770-4778.

Goetz CA, Harmon IR, O'Neil JJ, Burchill MA, Johanns TM, Farrar MA. Restricted STAT5 activation dictates appropriate thymic B versus T cell lineage commitment. J Immunol. 2005;174:7753-7763.

Will WM, Aaker JD, Burchill MA, Harmon IR, O'Neil JJ, Goetz CA, Hippen KL, Farrar MA. Attenuation of IL7R-dependent STAT5 Activation is not Required for Allelic Exclusion. J. Immunol. 2006;176:3350-3355.

Taylor DK, Walsh PT, LaRosa DF, Zhang J, Burchill MA, Farrar, MA, Turka LA. Constitutive activation of STAT5 supersedes the requirement for cytokine and TCR engagement of CD4+ T Cells in steady state homeostasis. J Immunol. 2006;177:2216-2223.

Seki Y, Yang J, Goizuka R, Farrar MA, Kubo M. IL-7/STAT5 cytokine signaling pathway is essential but insufficient for maintenance of naive CD4 T cell survival in peripheral lymphoid organs. J Immunol. 2007;178:280-290.

Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. Interleukin-2-receptor-dependent STAT5 activation is required for development of Foxp3+ regulatory T cells. J Immunol. 2007;178 262-270.

Burchill MA, Moon JJ, Chu HH, Vang KB, Lio C-WJ, Vegoe AL, Hsieh C-S, Jenkins MK, Farrar MA. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 2008;28:112-121.

Vang KB, Burchill MA, Vegoe AL, Farrar MA. Interleukin-2,-7 and -15 but not TSLP redundantly govern regulatory T cell development. J Immunol. 181:3285-3290.