Research Program:

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. 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.

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.

Lab members:
Ross Kedl
Phillip Sanchez, Postdoctoral fellow
Jason Oh, Doctoral Candidate
Jennifer McWilliams, Doctoral Candidate
Catherine Haluszczak, PRA

Representative publications:

• 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
• 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.
• 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 HIV Gag protein conjugated to a TLR7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in non-human primates. 2005 Proceedings of the National Academy of Sciences. 102(42):15190
• Phillip J. Sanchez, Catherin Haluszczak, and Ross M. Kedl. Coordinated integration of Toll Like Receptor and TNF-ligand pathways mediates potent adaptive immunity. 2006 Research Signpost: Towards an Understanding of Initiating T cell Immunity, Chapter 4 ISBN: 81-308-0118-3, 71-97.
• Ulrike Wille-Reece, Barbara J. Flynn, Karin Loré, Richard A. Koup, Aaron P. Miles, Allan Saul, Ross M. Kedl, Joseph J. Mattapallil, Walter R. Weiss, Mario Roederer, and Robert A. Seder. Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates. 2006 Journal of Experimental Medicine 203(5):1249-58.
• Jennifer A. McWilliams, Sean M. McGurran, 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. 2006 Journal of Immunology 177(1):155-161 .
• Phillip J. Sanchez, Catherine Haluszczak, Hideo Yagita, and Ross M. Kedl. Dendritic cell CD70 expression in vivo is regulated by combined TLR and CD40 stimulation and mediates CD8+ T cell expansion following immunization. 2006 Manuscript submitted

 

View of Recent Publications in PubMed