University of Nebraska-Lincoln School of Biological Sciences
142 Morrison Center
Lincoln, NE 68583-0900
Honors and Awards
USPHS Training grant (AI07285) trainee
USPHS Training grant (AI498) trainee
USPHS Fellowship grant (F32-AI056962)
Technical Associate University of Rochester Cancer Center 601 Elmwood Avenue, Box 704 Rochester, New York 14642, Laboratory of Dr. Richard P. Phipps
Pre-doctoral Candidate Department of Microbiology and Immunology University of Rochester 601 Elmwood Avenue, Box 672 Rochester, New York 14642 Advisor: Dr. Edith M. Lord
Fall semester, 1997 Teaching assistant
Post-doctoral Fellow Trudeau Institute, Inc. 154 Algonquin Ave. Saranac Lake, NY 12983 Mentor: Dr. Susan L. Swain
Adjunct Faculty Paul Smiths College Route 86 & 30 P.O. Box 265 Paul Smiths, NY 12970-0265
1. Brown, D. M., C. Kamperschroer, A. M. Dilzer, D. M. Roberts and S. L. Swain. 2009. IL-2 and antigen dose differentially regulate perforin- and FasL-mediated cytolytic activity in antigen specific CD4+ T cells. Cell Immunol.,257:69-79.
2. Brown, D. M. C. Kamperschroer, A. M. Dilzer, D. M. Roberts, and S. L. Swain. Unique conditions for generating cytolytic CD4+ T cells: IL-2 and antigen dose differentially regulate perforin- and FasL-mediated cytolytic activity. Submitted to J Immunol.
3. Jelley-Gibbs D. M., J. P. Dibble, D. M. Brown, T. M. Strutt, K. K. McKinstry and S. L. Swain. Persistent depots of influenza antigen fail to induce a cytotoxic CD8 T cell response. J Immunol. 178(12):7563-70, 2007.
4. Brown, D. M., A. M. Dilzer, D. L. Meents and S. L. Swain. CD4 T cell mediated protection from lethal influenza infection: perforin and antibody mediated mechanisms give a 1-2 punch. J Immunol, 177:2888-2898, 2006.
5. Jelley-Gibbs, D.M., D.M. Brown, J.P. Dibble, L. Haynes, S.M. Eaton, and S.L. Swain. Unexpected prolonged presentation of influenza antigens promotes CD4 T cell memory generation. J Exp Med 202:697-706, 2005.
6. Brown, D. M., E. Román and S. L. Swain. CD4 T cell responses to influenza infection. Seminars in Immunology, 16:171-177, 2004.
State University of New York at Geneseo, Geneseo, New York - B. S. in Biology, 1987
University of Rochester, School of Medicine and Dentistry, Rochester, NY - M. S. in Microbiology and Immunology, 1994 Ph.D. in Microbiology and Immunology, 2002
Our research project is focused on the host immune response to viral infections. Primarily, we use mouse models of influenza infection to understand how CD4 T cells are activated during infection and the mechanisms employed by these cells to help clear infectious virus. We also use a T cell receptor (TCR) transgenic (Tg) mouse model in which all of the CD4 T cells recognize a piece of the influenza virus and various "knock-out" mouse strains lacking important immune response genes to determine which type of CD4 T cell is important to provide protection against highly pathogenic influenza infections. Delineating the mechanisms whereby CD4 T cells provide protection to lethal influenza infections will further our understanding of CD4 T cell biology and provide a framework for developing novel vaccine formulations to combat highly pathogenic and emerging influenza virus strains.
In vitro studies: This project aims at understanding the activation and differentiation of a novel CD4 T cell subset that can kill virally infected cells. T cell receptor (TCR) transgenic (Tg) mice are invaluable tools for studying how T cells get activated both in vivo and in vitro. These mice have been genetically engineered such that all of the CD4 T cells possess an identical TCR and thus, can recognize the same antigenic peptide. For our in vitro studies, T cell receptor (TCR) transgenic (Tg) mice will be used in which all CD4 T cells recognize and respond to a peptide in hemagglutinin (HA), the outer coat protein of influenza. We also use TCR Tg mice in which the perforin gene has been deleted to understand how this cell death protein is regulated in CD4 T cells. We have demonstrated that antigen presenting cells (APC) either B cells or dendritic cells (DC), are necessary for the development of cytolytic activity by CD4 cells in vitro. Furthermore, the Th1 subset is cytolytic while Th2 polarization inhibits the cytolytic phenotype and the addition of IL-2 alone is sufficient to drive the differentiation of naïve CD4 cells into cytolytic effectors (Fig. 1). Studies are underway to determine the key molecule (cytokine or surface protein) expressed by B cells and DC that determines whether or not a CD4 cell will differentiate into the cytolytic subset. Furthermore, we hypothesize that DC drive perforin mediated cytolytic activity exclusively and are investigating whether certain toll like receptor ligands (TLR), that activate DC differently, have distinct effects on the generation of perforin mediated cytolytic activity by CD4 T cells.
In vivo studies: Past work has determined that CD4 T cells can promote survival against a highly lethal influenza virus, PR8, by both B cell dependent (antibodies) and B cell independent mechanisms (Brown, et al. 2006). The focus of this project will be to dissect the role of cytolytic CD4 cells in B cell independent protection against lethal influenza infection. Our hypothesis is that cytolytic CD4 cells can kill virally infected epithelial cells in the lung and contribute to viral clearance, even in the absence of B cells. Figure 2 demonstrates that CD4 cells can acquire perforin mediated cytolytic activity in vivo, and type II epithelial cells in the lung can express class II molecules in response to sublethal influenza infection. Furthermore, perforin expression in CD4 T cells abrogates weight loss in response to high dose infection in B cell deficient mice (Fig 2C). Studies are underway to determine if CD4 cells directly interact with, and use perforin to kill, virally infected epithelial cells in vivo.
Vaccine studies: The long-term goal of the in vitro studies is to determine the factors that regulate cytolytic CD4 T cell development as a prerequisite to developing vaccine strategies that target these cells. By targeting cellular mechanisms of protection, new vaccines could be developed that provide universal protection against serologically distinct and emerging influenza viral strains. Future projects will use recombinant DNA technology, specifically plasmid DNA and commercially available vectors to produce different influenza proteins in bacteria or in eukaryotic cells. Recombinant proteins conjugated to various toll like receptor (TLR) activating adjuvants will be injected into normal mice to determine the activation of primary and memory CD4 T cell populations that are important in providing protection against pathogenic influenza infection.