Summary of Research Interests

The laboratory is investigating how Toll Like Receptors (TLRs) generate innate immunity and how the nature of the innate response effects the generation of downstream adaptive immunity.

Much effort has gone into determining the minimal requirements and molecular pathways involved in creating the appropriate immunogenic context of antigen presentation. Since the time of Jenner (Edward, not Bruce) it has been recognized that the presentation of antigens in the context of a microbial or viral infection is potently immunogenic. It was later observed that this immunogenic activity can often be localized to the infectious material itself rather than the process of infection, eg. complete Freunds adjuvant and Coley’s toxin.

We now know that a good deal of this immunogenic activity is due to various microbial and viral products interacting with a family of mammalian molecules called Toll-like receptors (TLR) expressed predominantly on cells of the innate immune system. Since the identification of LPS as a TLR4 agonist by Beutler and colleagues, numerous other TLR agonists have been described such as tri-acyl lipopeptides (TLR1), peptidoglycan, lipoteichoic acid and Pam3cys (TLR2), dsRNA (TLR3), flagellin (TLR5), diacyl lipopeptides such as Malp-2 (TLR6), imidazoquinolines and single stranded RNA (TLR7, 8) and bacterial DNA, synthetic CpG DNA sequences, and even human genomic DNA antibody complexes (TLR9).

The involvement of TLRs in immunity is at least two fold, first as direct activators of innate immunity and second as initiators of adaptive immunity. TLR stimulation induces immediate innate effector functions and also creates the necessary conditions for the initiation of adaptive immunity. A dual role of TLRs in both innate and adaptive immunity has been confirmed in mice with genetic deletions of TLRs or TLR signaling molecules. Generally, mice with such deletions induce innate immunity less efficiently and have lower T and B cell responses to infection or vaccination than their wild type littermates.

Given the ability of many TLR agonists to mediate DC activation, cytokine production, costimulatory marker expression, and migration into T cell areas of lymphoid tissue, they appear to be optimal for use as vaccine adjuvants. However, when compared to an actual infection, the use of purified TLR agonists as vaccine adjuvants for the generation of T cell responses has been disappointing at best. Within 6-9 days after infection with many viruses or bacteria, either in animal models or in the clinic, the infected host often is capable of generating pathogen-specific T cell responses constituting 20-50% of the total circulating CD8+ T cells. In contrast, the generation of detectable T cell responses using only antigen and a TLR agonist(s) often requires multiple immunizations and even then the magnitude of the T cell response is rarely better than 5-10% of total circulating CD8+ T cells. Thus, the reduction of an infectious agent down to its antigens and TLR agonists does not reconstitute the magnitude of cellular immunity generated by the actual infection.

The lab is interested in both the normal stimuli and signals which initiate T cell activation and expansion in response to microbial/viral infection and how we can mimic those signals to produce better methods of vaccination. Given the link that TLRs make between the innate and adaptive response, they are obvious choices for use as modulators of T cell responses. Experimentally we have demonstrated a number of ways of using TLR agonists, singly and in combination with agonists for other stimulatory pathways, which result in potent T cell expansion, effector function, and memory generation. Additionally, we have begun to determine the molecular pathways which mediate this potent T cell expansion. These novel vaccination methods are being applied to both viral and tumor model systems in an effort to develop clinically relevant methods of therapeutic vaccination against diseases such as chronic infections and cancer.

Selected References:

• Ross M. Kedl, William A. Rees, David A. Hildeman, Brian Schaefer, John Kappler, and Philippa Marrack. T cells compete for access to antigen bearing antigen presenting cells. Journal of Experimental Medicine, 192(8):1105-1113 2000
• Ross M. Kedl, Michael Jordan, Terence Potter, John Kappler, Philippa Marrack, and Steven W. Dow. CD40 stimulation accelerates deletion of tumor-specific CD8(+) T cells in the absence of tumor-antigen vaccination. Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10811-6.
• Ross M. Kedl, Brian C. Schaefer, John W. Kappler, and Philippa Marrack. T cells down-modulate antigen/MHC complexes on antigen presenting cells in vivo. 2002 Nature Immunology 3(1):27-32
• Brian C. Schaefer, Michele L. Scheafer, John W. Kappler, Philippa Marrack, and Ross M. Kedl. Observation of antigen-dependent CD8+ T cell/dendritic cell interactions in vivo. 2002 International Immunology 214(2):110-22
• Sheila J. Gibson, Jana M. Lindh, Tony R. Riter, Ray M. Gleason, Lisa M. Rogers, Ashley E. Fuller, JoAnn L. Oesterich, Keith B. Gorden, Xiohong Qui, Scott W. McKane, Randy J. Noelle, Richard L. Miller, Ross M. Kedl, Patricia Fitzgerald-Borcarsly, Mark A. Tomai, and John P. Vasilakos. Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. 2002 Cellular Immunology 218:74-86
• Ross M. Kedl, John W. Kappler, and Philippa Marrack. Epitope dominance, competition and T cell affinity maturation. 2003 Current Opinion in Immunology 15:120-127
• Christie L. Doxsee, Tony R. Riter, Michael J Reiter, Shelia J. Gibson, John P. Vasilakos, and Ross M. Kedl. The Immune Response Modifier and TLR7 agonist S-27609 selectively induces IL-12 and TNF? production from CD11c+CD11b+CD8- dendritic cells 2003 Journal of Immunology 171(3):1156-1163.
• Cory Ahonen, Christie L. Doxsee, Sean McGurran, Tony R. Riter, Randolph J. Noelle and Ross M. Kedl. Combined TLR and CD40 Triggering Induces Potent CD8+ T Cell Expansion with Variable Dependence on Type I IFN. 2004 Journal of Experimental Medicine 199: 775–784.
• Keith B. Gorden, Kevin S. Gorski, Sheila J. Gibson, Ross M. Kedl, William C. Kieper, Xiaohong Qiu, Mark A. Tomai, Sefik S. Alkan, and John P. Vasilakos. 2005 Synthetic TLR Agonists Reveal Functional Differences between Human TLR7 and TLR8 2005 Journal of Immunology 174: 1259-1268
• Ulrike Wille-Reece, Chang-you Wu, Barbara J. Flynn, Ross M. Kedl and Robert A. Seder. 2005 Immunization with HIV-1 Gag protein conjugated to aTLR7/8 agonist results in the generation of HIV-1 Gag specific Th1 and CD8+ T cell responses Journal of Immunology 174:7676-7683
• Ulrike Wille-Reece, Barbara J. Flynn, Karin Lore, Richard A. Koup, Ross M. Kedl, Joseph J. Mattapallil, Mario Roederer, Walter R. Weiss and Robert A. Seder. Targeting Dendritic cell subsets influences Th1 responses and cross-presentation in monkeys. Manuscript submitted.
• Sean M. McGurran, Jennifer A. McWilliams, Steve W. Dow, Jill E. Slansky, and Ross M. Kedl. A modified TRP2 epitope generates high affinity tumor-specific T cells but does not mediate therapeutic efficacy. Manuscript submitted

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