Research Program: Immunology
Professor, Department of Medicine
Division Director, Division of Rheumatic and Autoimmune Diseases, Center for Immunology

muell002@umn.edu
612-625-1155 — office
612-625-8614 — lab
Preferred contact method: e-mail

Dr. Mueller's clinical profile
(University of Minnesota Physicians Web site)

Dr. Daniel Mueller is a Professor of Medicine, and Chief of Rheumatic and Autoimmune Diseases at the University of Minnesota Medical School. He undertook his medical studies at the University of Wisconsin-Madison School of Medicine, and later obtained his Internal Medicine training at the Ohio State University Hospital. In 1986, he received training in basic molecular immunology in the Laboratory of Immunology at the National Institute for Allergy and Infectious Disease, NIH, under Drs. Ronald Schwartz and William Paul. It is there that he initiated his research into fundamental mechanisms involved in the development and maintenance of immune self-tolerance. In 1990, Dr. Mueller entered the Rheumatology Training Program in the Rheumatic Diseases Division/Department of Internal Medicine at the University of Texas Southwestern Medical Center, under Dr. Peter Lipsky. Since the completion of his medical and research training, he has been on the University of Minnesota Medical School faculty. He is also a member of the Autoimmunity Program, within the University s Center for Immunology. The major focus of his academic program is the investigation of the biological and biochemical mechanisms that underlie the maintenance of T-cell tolerance within the peripheral immune system.

Research Interests

• T cell immune tolerance
• T cell clonal expansion
• Control of T cell function by histone modification

Current Research being conducted:

Autoimmunity develops as the consequence of a loss of tolerance to self-antigens. Investigations carried out by Dr. Daniel Mueller are leading to a better understanding of the biological and biochemical nature of immune self-tolerance. Of particular interest are those factors that determine whether prolonged and continuous antigen stimulation of a T-cell will lead to an increase in the clone size and the development of protective (or pathological) effector function, or lead to its functional inactivation (clonal anergy) and T-cell tolerance. Chronic antigen recognition in the absence of costimulatory ligands normally leads to clonal anergy induction, rather than aggressive immunity. This does not appear to be true, however, for individuals who are lymphopenic, where antigen recognition invariably leads to an expansion of the clone, continued functional responsiveness, and in some case immunopathology. Recent experimental observations from his laboratory, and others, have suggested a role for single chain E3 ligases in this counter-regulation of clonal expansion and induction of clonal anergy. Other recently published studies in the laboratory have defined the importance of ongoing antigen recognition within peripheral tissues to facilitate the accumulation of effector T-cells capable of inducing tissue damage. Currently, these biological principles are being investigated in the setting of T cell-mediated inflammatory arthritis using KRN transgenic T cells. Finally, experiments are underway that investigate the mechanisms by which histone modifications regulate gene transcription and promote the development of the clonal anergy state.

Selected Publications

Bonnevier JL, Zhang R, Mueller DL. E3 ubiquitin ligases and their control of T cell autoreactivity. Arthritis Res Ther. 2005;7:233-242. Review.

Lande JD, Dalheimer SL, Mueller DL, Hertz MI, King RA. Gene expression profiling in murine obliterative airway disease. Am J Transplant. 2005;5:2170-2184.

Dalheimer SL, Richards DM, Mueller DL. Sharing of class I MHC molecules between donor and host promotes the infiltration of allografts by mHAg-reactive CD8 T cells. Am J Transplant. 2005;5(4 Pt 1):832-838.

Colombetti S, Basso V, Mueller DL, and Mondino A. Prolonged TCR/CD28 engagement drives IL-2-independent T cell clonal expansion through signaling mediated by the mammalian target of rapamycin. J Immunol. 2006;176:2730-2738.

Vanasek TL, Nandiwada S, Jenkins MK, and Mueller DL. CD25+ Foxp3+ regulatory T cells facilitate CD4+ T cell clonal anergy induction during the recovery from lymphopenia. J Immunol. 2006;176:5880-5889.

Bonnevier JL, Yarke CA, and Mueller DL. Sustained B7/CD28 interactions and resultant phosphatidylinositol 3-kinase activity maintain G1-->S phase transitions at an optimal rate. Eur J Immunol. 2006;36:1583-1597.

Nandiwada SL, Li W, Zhang R, and Mueller DL. p300/Cyclic AMP-responsive element binding (CREB)-binding protein mediates transcriptional co-activation by the CD28 T cell costimulatory receptor. J Immunol. 2006;177:401-413.

Mueller DL. Linking diacylglycerol kinase to T cell anergy. Nature Immunol. 2006;7:1132-1134.

Mueller DL. Molecular mechanisms supporting peripheral T cell tolerance: Potential therapeutic approaches to autoimmunity and allograft rejection. Sem Immunol. 2007;19:139.

Mondino A, and Mueller DL. mTOR at the crossroads of T cell proliferation and tolerance. Sem Immunol. 2007;9:162-172.

Richards DM, Zhang N, Dalheimer SL, and Mueller DL. Allopeptide-specific CD4+ T cells help directly alloreactive graft-infiltrating CD8+ T cells in the absence of APC licensing. Am J Transplant. 2007;7:2269-2278.

Yarke CA, Dalheimer SL, Zhang N, Catron DM, Jenkins MK, and Mueller DL. Proliferating CD4+ T cells undergo immediate growth arrest upon cessation of TCR signaling in vivo. J Immunol. 2008;180:156-162.

Obhrai JS, Oberbarnscheidt M, Zhang N, Mueller DL, Shlomchik WD, Lakkis FG, Shlomchik MJ, Kaplan DH. Langerhans cells are not required for efficient skin graft rejection. J Invest Dermatol. 2008;128:1950-1955.

Zhang R, Zhang N, Mueller DL. Casitas B-lineage lymphoma b inhibits antigen recognition and slows cell cycle progression at late times during CD4+ T cell clonal expansion. J Immunol. 2008 Oct 15;181(8):5331-9.