University of Nebraska-Lincoln School of Biological Sciences
142 Morrison Center
Lincoln, NE 68583-0900
My main teaching responsibility is the undergraduate/graduate level Immunology course in the School of Biological Sciences (BIOS 443/843). This is an introductory level course designed to give students an overall understanding of immune processes from the recognition of invading pathogens by innate immune cells and the development and activation of the adaptive arm of the immune response. An exceprt from the syllabus for BIOS 443/843 follows: My goal for this course is to provide you with an understanding of basic immunology concepts and an exposure to the breadth of the field of immunology research. You should develop a solid understanding of the two arms of the immune response (innate vs adaptive), how they interact to rid the body of pathogens and how this response is regulated. We will also cover major concepts in immunology such as the clonal selection theory and how antigen receptors are generated, mechanisms of central and peripheral tolerance induction, innate immune defenses and the activation of the adaptive, antigen specific immune response. At the end of this course students should be able to: 1) Understand the differences between the innate and adaptive immune system and how each response cooperates to rid the body of harmful pathogens. 2) Understand the concept of the clonal selection theory and how lymphocytes are generated with an infinite number of different antigen receptors from a relatively small number of genes. 3) Conceptualize the mechanisms of peripheral and central tolerance and how these mechanisms aid in the development of the lymphocyte repertoire, while protecting the body from attacking itself. 4) Describe how B cells and T cells exert different effector functions to handle different pathogens or different types of antigens. 5) Use your knowledge of immunology and critical thinking skills to solve research problems. Students in BIOS 443/843 are exposed to a variety of teaching approaches including classical lectures supplemented with animations and graphics, in-class activities and “Jeopardy” style exam review. In a curriculum that involves problem-based learning, students are expected to apply the framework of knowledge provided to them by answering questions they may not have thought about before. To this end, Just in Time Teaching, or JiTT techniques will require students to prepare reading assignments and answer specific concept related questions, linking new material or ideas with previously learned concepts. The student responses are directly used during lecture to facilitate discussion of the topic. Importantly, at least one open-ended reflective question should be used, making JiTT an effective tool to promote critical thinking and ownership of student learning. A new course for graduate students will be offered in Spring 2014, Advanced Topics in Immunology: Vaccine Biology. This course will be discussion based, with graduate students reading primary literature and critically reviewing data and conclusions. Review articles and short lectures will complement discussions. A syllabus for this course will be coming soon!
Honors and Awards
AAI Junior Faculty Travel Grant
UNL Parents Association, Recognition for Contribution to Students
AAI Junior Faculty Travel Grant
AAI Junior Faculty Travel Grant
April, 2004- April, 2005
USPHS Fellowship grant (F32-AI056962)
Nov., 2001-April, 2004
USPHS Training grant (T32-AI498) trainee
USPHS Training grant (T32-AI07285) trainee
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
- Moore, T. C., K. Bush, E. Cody, D. M. Brown and T. M. Petro. 2012. Interleukin-6 control of early Theiler's Murine Encephalomyelitis Virus replication in macrophages occurs in conjunction with STAT1 activation and nitric oxide production. J Virology, 86:10841-51.
- Gangaplara A., C. Massilamany, D. M. Brown, G. Delhon, A. K. Pattnaik, N. Chapman, N. Rose, D. Steffen and J. Reddy. 2012. Coxsackievirus B3 infection leads to the generation of cardiac myosin heavy chain-α-reactive CD4 T cells in A/J mice. Clin Immunol. 144(3):237-49.
- McKinstry, K. K., T. M. Strutt, Y. Kuang, D. M. Brown, S. Sell, R. W. Dutton and S. L. Swain. 2012. Memory CD4+ T-cells protect against influenza by multiple synergizing mechanisms J Clin Invest, 122:2847-56.
- Brown, D. M., S. Lee, M. L. Garcia-Hernandez, and S. L. Swain. 2012. Multi-functional CD4 cells expressing IFN-g and perforin mediate protection against lethal influenza infection. J Virology 86:6792-803.
- Moore, T. C., F. M. Al-Salleeh, D. M. Brown, and T. M. Petro. 2011. IRF3 Polymorphisms Induce Different Innate Anti-Viral Immune Responses in Macrophages. Virology, 418(1):40-8.
- Brown, D. M. 2010. Cytolytic CD4 Cells: Direct mediators in infectious disease and malignancy. CelI Immunol. 262:89-95.
- 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.
- Jelley-Gibbs D. M., J. P. Dibble, D. M. Brown, T. M. Strutt, K. K. McKinstry and S. L. Swain. 2007. Persistent depots of influenza antigen fail to induce a cytotoxic CD8 T cell response. J Immunol. 178(12):7563-70.
- Agrewala, J. N., D. M. Brown, N. M. Lepak, D. Duso, G. Huston and S. L. Swain 2007. Unique Ability of Activated CD4+ T Cells but Not Rested Effectors to Migrate to Non-lymphoid Sites in the Absence of Inflammation. J Biol Chem. Mar 2;282(9):6106-15. Epub 2006 Dec 29.
- 10. Brown, D. M., A. M. Dilzer, D. L. Meents and S. L. Swain. 2006. CD4 T cell mediated protection from lethal influenza infection: perforin and antibody mediated mechanisms give a 1-2 punch. J Immunol, 177:2888-2898.
- Swain SL, Agrewala, JN, Brown DM, Jelley-Gibbs DM, Golech S, Huston G, Jones SC, Kamperschroer C, Lee W-H, McKinstry K, Roman E, Strutt T. and Weng N-P. 2006. CD4 Memory: Generation and Multi-faceted Roles for CD4 T Cells in Protective Immunity to Influenza. Immunological Reviews, 211:8-22
- Crowe, S.R., S.C. Miller, D.M. Brown, P.S. Adams, R.W. Dutton, A.G. Harmsen, F.E. Lund, T.D. Randall, S.L. Swain, and D.L. Woodland. 2006. Uneven distribution of MHC class II epitopes within the influenza virus. Vaccine 24:457-467.
- Jelley-Gibbs, D.M., D.M. Brown, J.P. Dibble, L. Haynes, S.M. Eaton, and S.L. Swain. 2005. Unexpected prolonged presentation of influenza antigens promotes CD4 T cell memory generation. J Exp Med 202:697-706.
- Brown, D. M., E. Román and S. L. Swain. 2004. CD4 T cell responses to influenza infection. Seminars in Immunology, 16:171-177.
- Powell, T. J., D. M. Brown, J. Hollenbaugh, R. A. Kemp, T. Charbonneau, S. L. Swain and R. W. Dutton. 2004. CD8+ T cells responding to influenza infection reach and persist at higher numbers than CD4+ T cells independently of precursor frequency. J. Clin. Immunol. 113, 89-100.
- Swain, S.L., J.N. Agrewala, D. M. Brown, and E. Roman. 2002. Regulation of Memory CD4 T Cells: Generation, Localization and Persistence. In Lymphocyte Activation and Immune Regulation IX – Homeostasis Lymphocyte Traffic. S. Gupta, E. Butcher and W. Paul, editors. Kluwer Academic/Plenum Publishers, New York, NY. 113-120.
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 laboratory is interested in the immune response to viral infections, specifically focusing on the CD4+ T cell response to influenza. My post-doctoral studies at the Trudeau Institute determined that CD4 T cells contribute to clearance of highly pathogenic influenza virus by more direct mechanisms than has previously been appreciated. We have shown that CD4 cells acquire perforin mediated cytotoxicity that has historically been restricted to CD8+ killer cells. It is this unique characteristic of CD4 T cell function that forms the basis of our research program here at UNL. The overall goal of our research is to understand the innate signals that promote the differentiation of protective CD4 T cell responses to ultimately facilitate the design of new vaccine strategies against existing and emerging infectious diseases. Our research program is designed to answer the following questions:
1) what are the cytokine and inflammatory signals that drive the differentiation of CD4 CTL in vivo in response to influenza infection?
2) do CD4 CTL represent a unique subset of CD4 T cell effectors?
3) can CD4 CTL be induced by vaccination and persist as memory cells?
4) do CD4 CTL act to decrease viral titers directly, or suppress macrophage inflammation at the site of infection?
We have developed unique in vitro and in vivo models to investigate the generation and regulation of cytolytic CD4 T cells (CD4 CTL) and have shown that IL-2 may be the master regulator of CD4 CTL differentiation. In vivo evidence also confirms that IL-2 signaling is necessary for GrB expression during influenza infection, but higher inflammatory responses provided by high dose infection overcomes the requirement for IL-2. We are actively pursuing the inflammatory mediators that may be responsible for driving cytolytic activity in CD4 T cells.
Influenza infection remains a serious health concern due to increased mortality and morbidity in infants, the elderly and immunocompromised individuals. In addition, recent outbreaks of antigenically distinct influenza strains have achieved pandemic status (2009 H1N1) and underscore the need for more effective vaccine strategies. Current vaccines induce high affinity antibodies that target the outer viral coat proteins: hemagglutinin (HA) and neuraminidase (NA), however, these proteins are the most susceptible to mutation and have been the driving force of pandemics in the last century. In contrast, T cells recognize the inner proteins of the virus such as nucleoprotein (NP) and acid polymerase (PA). These proteins are more conserved between different influenza strains and do not undergo mutation as readily. Therefore, there is much interest in developing vaccines that target conserved, internal proteins of influenza leading to cross protective, heterosubtypic T cell immunity. To that end, we have begun a new project to determine which innate immune pattern recognition receptors (PRRs) and cytokines are responsible for inducing CD4 CTL in vivo and whether vaccine strategies that target those receptors could induce CD4 CTL that contribute to protection. We are using an agonist (CpG) that activates TLR-9 as a vaccine strategy to induce T cell activation and memory formation that could ultimately provide protection against lethal infection. We have found that vaccination with CpG + inactivated virus significantly reduces viral titers (Fig. 1D) and promotes survival (data not shown) upon challenge with lethal influenza infection. Immunization with low dose, live influenza infection serves as a positive control for clearance of virus and survival upon lethal challenge, while PBS and inactivated virus alone are negative controls showing high viral titers and mortality. Correlating with lower viral titers and survival is a robust T cell response to the lung upon lethal challenge (Fig 1). Both CD8 and CD4 T cells expressing GrB are at higher numbers in the lung after CpG vaccination and lethal challenge compared to vaccination with inactivated virus alone (Fig 1A and 1B). Higher numbers of CD4 cells expressing IFN-g were also observed in mice receiving CpG vaccination compared to inactivated virus alone (Fig 1C). These results suggest CpG vaccination induces T cell mediated immunity that provide protection against lethal influenza infection. Future studies will determine whether T cells are required for protection in our model.