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Research > Faculty By Division > Mark Miller, PhD

Assistant Professor, Pathology and Immunology
West Building
Office: (314) 362-3044
Lab: (314) 362-3166,
E-mail: mmiller23@wustl.edu
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Research

The immune system must respond rapidly and efficaciously to microbial infection, yet this response must avoid becoming pathogenic to the host. In this context, regulatory T cells (T regs; CD4+ CD25+, FoxP3 expressing T cells) play a central role in regulating adaptive immune responses to ensure that tolerance to host tissues is maintained. A case in point is that autoimmune disease develops in both humans and mice deficient in T regs. Conversely, depletion of T regs has been shown to augment the immune response to cancer. The regulatory action of T regs involves the cytokines IL-10 and TGF-?. Moreover, cell-to-cell contact appears to be required for the suppression of T cell proliferation in vitro. However, virtually nothing is known about the cellular specificity, stoichiometry, kinetics or location of immunoregulatory events in vivo. With recent advances in multi-photon microscopy, complex cellular interactions can now be studied directly in native tissues. Our approach is to use single-cell imaging to assess T reg impact on antigen presentation, T cell activation and effector function. We are currently developing two complementary mouse models for this purpose. With the first system we will investigate the role of T regs in the rejection or progression of implanted primary tumors. In the second model, we will examine the regulation of T cell responses during Listeria infection. Our hope is that comparing and contrasting T cell regulation in these systems will provide useful insight for how tolerance and immunity are governed.

A secondary interest in the lab is to use biophysical data obtained by multi-photon microscopy to develop tissue level models for T cell regulation. The potential synergy between imaging and computational biology is tremendous i.e., computer simulations will guide experimental design, and in situ imaging will provide solid quantitative data for model refinement.


Selected Publications

Zinselmeyer BH, Dempster J, Gurney AM, Wokosin D, Miller MJ, Ho H, Millington OR, Smith KM, Rush CM,. In situ characterisation of CD4+ T cell behaviour in lymphoid tissues during the induction of oral priming and tolerance. J Exp Med 201:1815-1823, 2005 Abstract

Okada T, Miller MJ, Parker I, Krummel MF, Neighbors M, Hartley SB, O'Garra A, Cahalan MD, Cyster JG. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS Biol 3:e150, 2005 Abstract

Miller MJ, Safrina O, Parker I, Cahalan MD. Imaging the single-cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. J Exp Med 200:847-856, 2004 Abstract

Miller MJ, Hejazi AS, Wei SH, Cahalan MD, Parker I. T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in lymph nodes. Proc Natl Acad Sci USA 101:998-1003, 2004 Abstract

Cahalan MD, Parker I, Wei SH, Miller MJ. Real-time imaging of lymphocytes in vivo. Curr Opin Immunol 15:372-377, 2003 Abstract

Miller MJ, Wei SH, Cahalan MD, Parker I. Autonomous T cell trafficking examined in vivo with intravital two-photon microscopy. Proc Natl Acad Sci USA 100:2604-2609, 2003 Abstract

Cahalan MD, Parker I, Wei SH, Miller MJ. Two-photon tissue imaging: seeing the immune system in a fresh light. Nat Rev Immunol 2:872-880, 2002 Abstract

Wei SH, Miller MJ, Cahalan MD, Parker I. Two-photon imaging in intact lymphoid tissue. Adv Exp Med Biol 512:203-208, 2002 Abstract

Miller MJ, Wei SH, Parker I, Cahalan MD. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296:1869-1873, 2002 Abstract


Past Trainees

Taiki Aoshi