Research and Professional Experience:
1976-1977 Lecturer, UCSD, La Jolla, CA
1976-1981 Assistant Research Biologist, UCSD
1981-1984 Associate Research Biologist, UCSD
1984-1989 Associate Professor of Biology in Residence, UCSD
1989-1995 Professor of Biology in Residence, UCSD
1985-1996 Member, UCSD Cancer Center, San Diego, CA
1996-2007 Director, Trudeau Institute, Saranac Lake, NY
1996-present Member, Trudeau Institute, Saranac Lake, NY
1996-2007 Edward C. Brewster Chair, Trudeau Inst., Saranac Lake, NY
1998-present Adjunct Professor, Dept of Micro, Immunol & Mol. Gen, Albany Medical College, Albany, NY
2001-present Adjunct Professor, University of Vermont College of Medicine, Burlington, VT
2003-2007 President,Trudeau Institute, Saranac Lake, NY
2008-2010 President Emeritus, Trudeau Institute
2010 Professor of Pathology, UMASS Medical School, Worcester, MA
Study Sections and Advisory Panels: Past:NIH Immunobiology Study Section (1984-1988); AIDS Basic Research Advisory Committee, NIAID (1990-1992); National Taskforce on Aging, NIA/NIAID (1994); FY1997 AIDS Planning Committee (1995); Ad Hoc Member, Board of Scientific Councilors NIAID (1995, 2000); Scientific Advisory Board, Inst. for Advanced Studies in Immunol. Aging (1996-1999); Reviewer's Reserve, NIH (1988-present); NHLBI SCOR Review in Asthma Panel (2001); Board of Scientific Councilors, National Institute of Aging (2001-2006), Arthritis Review Panel in Cellular Immunology (1996-1998); Board of Trustees, Ordway Institute, Albany, NY (2001-2005), External Advisory Committee, University of Montana COBRE (2005-2007). External Advisory Board Duke University Dept. of Immunology (2008), Current: Board of Directors La Jolla Institute of Allergy and Immunology (2004-present), Selection Committee Albany Medical Prize (2005-present), External Advisory Committee (EAC): Wistar BAA (2006-present) and Dartmouth University COBRE (2007-present). National Advisory Council on Aging 2008-2012, Scientific Advisory Board La Jolla Institute of Allergy and Immunology 2008-present, Advisory Group Aeras 2007-present, Distinguished Editorial Panel NIAID (2009), Council, NIAID (Ad Hoc, 2009)
Editorial Boards:Past: Lymphokines (1985-1988); Journal of Immunology Associate Editor (1985-1987), Section Editor (1987-1991), Primary Reviewer (1997-present); International Immunology (1988-present); Cellular Immunology (1988-present); Cell (1990-1992); Current Opinion in Immunology, issue editor (1994, 1996, 2003, 2009); Current Biology (1994), Journal of Experimental Medicine (1997-2008), Current: Deputy Editor, Journal of Immunology 2008-2012, Faculty of 1000, Section Leader (2002-present).
Meeting Organization: Workshop on T and B Cell Memory (1993, 1998); Midwinter Immunology Conference Council (1992), Midwinter Conference of Immunologists (1996); Keystone Symposium on Lymphocyte Activation (1996); International Cytokine Conference (1997); Delegate IUIS (2002-2006), Workshop on Immunity and Aging, Trudeau Institute, NY (2004); Cold Spring Harbor Vaccine Meeting (2005, 2007, 2009), Keystone Symposium on Immunological Memory (2007), FASEB Summer Conference (2008, 2010).
Community Service:American Association of Immunology: Committee on Women (1988-1994), Program Committee (1988-1994); Chair, T Cell Block for FASEB Meeting (1992-1995); Nominations Committee (Elected, 1991, 1995,1996). Publication Committee (Elected, 1994-1998).
Elected Positions: Council Member, American Association of Immunologists (1999-2006); Electorate Nominating Committee of the Section on Medical Sciences, AAAS (2004); President, American Association of Immunologists (2004).
Honors and Awards:Phi Beta Kappa, Magna Cum Laude, B.A. (1968); Sigma Xi (1972); Established Investigator, American Heart Association (1981-1986); NIH Merit Award (1995, 2005); New York State Woman of Distinction (2002); Fellow of the American Association for Advancement of Science (2007); American Association of Immunologists Lifetime Achievement Award (2010).
Our past research has focused on defining the cellular and molecular mechanisms by which CD4 T cells contribute to immunity. In particular we have 1) Defined, generated and determined the function of T cell subsets at the effector stage; 2) Studied the requirements for the generation of long-live memory CD4 T cells and their role in protection against influenza infection and 3) Analyzed the defects that develop in T cell function with aging and the causes of those defects.
Our top priorities at this time are to discover new basic cellular and molecular mechanisms that are used by memory CD4 T cells to provide effective immunity to infectious diseases and to better define the age-associated defects in CD4 T cells that contribute to poor immunity of the aged and to discover strategies to overcome those defects.
Rotations: Projects in the following areas
CD4 T cell memory. We can generate in vitro CD4 T cells that are for all extents and purposes identical to the memory CD4 T cells observed in vivo. In situ memory CD4 T cells persist at very low frequency and in most instances it is difficult to analyze them thoroughly using tetramer or multimer reagents both because of their low frequency and the relatively low specific affinity of the Class II reagents for the TcR. Being able to generate “recent” memory cells in vitro gives us the opportunity to analyze in detail the mechanisms by which memory CD4 T cells may contribute to secondary immunity and immune protection. Once identified. will determine if particular pathways are relevant in situ. We have discovered that memory CD4 T cells are superior in protection to those from the primary response and that they display pleitropic functions that have not been previously identified.
Cytotoxic CD4 Effectors. One unexpected function of CD4 T cells we identified is robust, perforin-dependent cytotoxic activity (7, 16). Cytotoxic activity by CD4 T cells has been reported in response to several infections, but its significance has not heretofore been established. We find that “Th1 polarized” CD4 effectors and more relevantly the CD4 effectors found in the lung following influenza infection, are able to kill infected or peptide-pulsed Class II-bearing targets and we find that this perforin dependent activity can work together with antibody to provide protection against lethal influenza challenge in otherwise unprimed mice (17). We also will determine when memory CD4 T cells re-express cytotoxic activity following in vivo challenge and how cytotoxic killing contributes to the memory cell mediated protection. We want to analyze how the program of cytotoxicity is induced in these “ThCTL”.
Memory CD4 Cells Enhance an Innate Response. Memory cells can act by becoming secondary effectors but they are best characterized by their ability respond rapidly even to low antigen doses, by producing cytokines and chemokines and it is assumed that these initial abilities are key to memory cell activity. However this assumption has not been directly demonstrated and the mechanisms involved and how they might contribute to immunity have not been elucidated. We find that restimulation of memory CD4 T cells leads to a markedly enhanced early innate response to influenza infection both in the lung and systemically (17). This response peaks 2-3 days after infection and is transient. We see enhanced production of IL-6 locally and systemically and enhanced production a broad spectrum of innate inflammatory mediators in the lung. We hope to determine in detail the pathways leading to optimum memory T cell-induced innate responses. We suggest a concurrent activation of CD4 memory cells may be an effective adjuvant for vaccination and will be testing this hypothesis as well as mechanisms that lead to viral control over the next couple of years.
Aging and Immunity: The study of the impact of aging on CD4 T cell function at the naïve and memory stages has lead us to better understanding of fundamental aspects of T cell behavior in addition to providing important information about what vaccine approaches are most likely to be successful for the aged.
Nature of CD4 Aging “Defects”. We have identified multiple levels at which aged naïve CD4 T cells are defective including initial early response to TcR triggering, IL-2 production, expansion and effector generation. The defects in helper function and in the 20 response of memory cells generated from aged naïve CD4 T cells are particularly dramatic. In recent studies we have recapitulated memory age-associated defects in recently generated memory cells in vitro (23). In vitro aged memory cells are markedly defective in production of particular cytokines, IL-4, IL-5 and IL-2, while others are little affected (IFNg, IL-10, TNF), suggesting the aging “defect” may be restricted to loss of potential to make certain CD4 T cell subsets, such as those responsible for help to B cells .We will pursue this hypothesis both in vitro and in vivo.
We have found that aged naïve CD4 T cells are in fact longer-lived than their naïve counterparts (23). We find that reduced expression of Bim, a proapoptotic protein, is responsible for this increase in lifespan and that the increase in lifespan is required for the development of aging defects. We are now investigating the factors that regulate Bim expression.
Enhancement by Inflammatory Cytokines. We have shown that the defective effector generation responses of naïve CD4 T cells from aged animals can be overcome by IL-2 and by proinflammatory cytokines, in particular a mix of IL-1, IL-6 and TNF (20,21). We want to determine the extent to which the inflammatory cytokines can reverse the heritable aging defects and restore functional memory generation. We have developed in vitro models to test the generation of effectors and memory. In these models we are evaluating TLR agonists for their ability to restore aged naïve CD4 responses to peptide-pulsed derived dendritic cells (DC). Pre-incubation of DC with many TLR agonists, enhances expansion of the responding aged naïve CD4 T cells via a mechanism dependent on IL-6 that acts in part by increasing survival of the developing effector population. We plan to use this model to identify the extent of the rescue and what pathways and mechanisms contribute with the ultimate goal of evaluating whether specific TLR stimulation or stimulation of specific pathways might improve the response of the elderly to vaccines. We want to see if we can reproduce this model with human naïve CD4 T cells and DC derived from peripheral blood and if TLR agonists can also enhance those responses.